Scholars@Duke
Walter J. Koch

Walter J. Koch

Professor in Surgery
Surgery, Cardiovascular and Thoracic Surgery
walter.koch@duke.edu
Box 102155, Durham, NC 27710
487 CARL Building, 213 Research Drive, Durham, NC 27710

Selected Publications

GRK2 and GRK5-The 2 critical kinases in cardiac pathophysiology.

Journal Article Mol Pharmacol · November 29, 2025 G protein-coupled receptor kinases (GRKs) are a class of serine/threonine kinases that shut down active signaling mediated by agonist-bound G protein-coupled receptors. Of all the diseases that arise from dysfunctional G protein-coupled receptor-GRK intera ... Full text Link to item Cite

Cardiac-Targeted AAV5-S100A1 Gene Therapy Protects Against Adverse Remodeling and Contractile Dysfunction in Postischemic Hearts.

Journal Article Circ Heart Fail · July 2025 BACKGROUND: Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysfunctional human-sized hearts, using ... Full text Link to item Cite

Hepato-cardiac interorgan communication controls cardiac hypertrophy via combined endocrine-autocrine FGF21 signaling.

Journal Article Cell Rep Med · June 17, 2025 Fibroblast growth factor (FGF) 21 is a hormone produced mainly by the liver but also other organs, including the heart. Although FGF21 analogs are used for treating obesity and metabolic syndrome in humans, preclinical and clinical studies have elicited mi ... Full text Link to item Cite

S100A1ct: A Synthetic Peptide Derived From S100A1 Protein Improves Cardiac Performance and Survival in Preclinical Heart Failure Models.

Journal Article Circulation · February 25, 2025 BACKGROUND: The EF-hand Ca2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca2+ ATPase ... Full text Link to item Cite

Adipocyte-derived small extracellular vesicles exacerbate diabetic ischemic heart injury by promoting oxidative stress and mitochondrial-mediated cardiomyocyte apoptosis.

Journal Article Redox Biol · February 2025 BACKGROUND: Diabetes increases ischemic heart injury via incompletely understood mechanisms. We recently reported that diabetic adipocytes-derived small extracellular vesicles (sEV) exacerbate myocardial reperfusion (MI/R) injury by promoting cardiomyocyte ... Full text Link to item Cite

Therapeutic Efficacy of a Novel Pharmacologic GRK2 Inhibitor in Multiple Animal Models of Heart Failure.

Journal Article JACC Basic Transl Sci · February 2025 GRK2 is the most prominent G protein-coupled receptor kinase that is upregulated in heart failure (HF), and inhibiting GRK2 has improved cardiac function in mice. CCG258208, generated from the paroxetine scaffold, which has GRK2 inhibitory properties, has ... Full text Link to item Cite

Phosphoserine aminotransferase 1 promotes serine synthesis pathway and cardiac repair after myocardial infarction.

Journal Article Theranostics · 2025 Background and Purpose: The permanent loss of cardiomyocytes (CMs) following myocardial infarction (MI), coupled with the heart's limited regenerative capacity, often leads to heart failure. Phosphoserine aminotransferase 1 (PSAT1) is a protein highly expr ... Full text Link to item Cite

Editorial Overview: Adrenergic signaling in cellular physiology and disease

Journal Article Current Opinion in Physiology · December 1, 2024 Full text Cite

GPC3-mediated metabolic rewiring of diabetic mesenchymal stromal cells enhances their cardioprotective functions via PKM2 activation.

Journal Article iScience · October 18, 2024 Mesenchymal stromal cells (MSC) are promising stem cell therapy for treating cardiovascular and other degenerative diseases. Diabetes affects the functional capability of MSC and impedes cell-based therapy. Despite numerous studies, the impact of diabetes ... Full text Link to item Cite

Correction to: Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury

Journal Article Arteriosclerosis, Thrombosis, and Vascular Biology · October 2024 Full text Cite

Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.

Journal Article Circ Res · July 5, 2024 BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles, including small extracellular vesicles or exosomes, and their molecular cargo are known to modulate cell-to-cell communication during multiple cardi ... Full text Link to item Cite

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction.

Journal Article bioRxiv · July 2, 2024 BACKGROUND: Amyloidosis is a major long-term complication of chronic disease; however, whether it represents one of the complications of post-myocardial infarction (MI) is yet to be fully understood. METHODS: Using wild-type and knocked-out MI mouse models ... Full text Link to item Cite

Epigenetic mechanisms regulate sex differences in cardiac reparative functions of bone marrow progenitor cells.

Journal Article NPJ Regen Med · April 29, 2024 Historically, a lower incidence of cardiovascular diseases (CVD) and related deaths in women as compared with men of the same age has been attributed to female sex hormones, particularly estrogen and its receptors. Autologous bone marrow stem cell (BMSC) c ... Full text Link to item Cite

Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury.

Journal Article Arterioscler Thromb Vasc Biol · December 2023 BACKGROUND: APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications ... Full text Link to item Cite

Abstract 16052: Non-Canonical Mechanisms of BARKct-Mediated GRK2 Inhibition in Heart Failure Rescue

Conference Circulation · November 7, 2023 Introduction: Significant GRK2 upregulation during HF results in desensitization of βARs. βARKct is a peptide inhibitor of GRK2 comprised of the last carboxyl terminal region of GRK2, and prevents GRK ... Full text Cite

GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion.

Journal Article Journal of molecular medicine (Berlin, Germany) · November 2023 Reperfusion after acute myocardial infarction further exaggerates cardiac injury and adverse remodeling. Irrespective of cardiac cell types, loss of specifically the α isoform of the protein kinase GSK-3 is protective in chronic cardiac diseases. However, ... Full text Cite

Hypoadiponectinemia-induced upregulation of microRNA449b downregulating Nrf-1 aggravates cardiac ischemia-reperfusion injury in diabetic mice.

Journal Article J Mol Cell Cardiol · September 2023 Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incomple ... Full text Link to item Cite

Abstract P3152: Diabetic Upregulation Of Grk2 Impairs Adipocyte Exosome Surface Adiponectin-mediated Cardioprotection And Exacerbates Ischemic Heart Failure

Conference Circulation Research · August 4, 2023 Background: Type 2 diabetes mellitus (DM) significantly exacerbates ischemic heart failure (IHF) by incompletely understood mechanisms. We recently reported that DM switches adipocyte-derived exosome ... Full text Cite

Abstract P2117: Hypoadiponectinemia-induced Epigenetic Downregulation Of Endogenous Antioxidants Exacerbates Cardiac Ischemia-reperfusion Injury In Diabetic Mice

Conference Circulation Research · August 4, 2023 Diabetes worsen myocardial ischemic/reperfusion (MI/R) injury, but the underlying mechanism is still not fully understood. Epigenetics regulation is markedly involved in the process. Adiponectin (APN), a cardioprotective adipokine, is suppressed by ... Full text Cite

Abstract P2033: Western Diet Can Cause Adverse Cardiac Remodeling During Pregnancy By Inducing Foxo1 Expression

Conference Circulation Research · August 4, 2023 Introduction: Pregnancy induces physiological cardiac hypertrophy in healthy women. Our recent findings suggest that obesity can disturb this process and induce pathological cardiac hypertrophy during ... Full text Cite

Abstract 450: Map Kinase Phosphatase-5 Deficiency Impairs Efferocytosis And Exacerbates Late-Stage Atherosclerosis

Conference Arteriosclerosis, Thrombosis, and Vascular Biology · May 2023 Objective: Atherosclerosis is a vascular inflammatory disease that is the leading cause of death worldwide. Late-stage atherosclerotic plaque contains a thin fibrous cap and a large necrotic core that ... Full text Cite

Novel roles for G protein-coupled receptor kinases in cardiac injury and repair.

Journal Article Biochem Soc Trans · April 26, 2023 G protein-coupled receptors (GPCRs) are key modulators of cell signaling. Multiple GPCRs are present in the heart where they regulate cardiac homeostasis including processes such as myocyte contraction, heart rate and coronary blood flow. GPCRs are pharmac ... Full text Link to item Cite

Nitrative Modification of Caveolin-3: A Novel Mechanism of Cardiac Insulin Resistance and a Potential Therapeutic Target Against Ischemic Heart Failure in Prediabetic Animals.

Journal Article Circulation · April 11, 2023 BACKGROUND: Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, includ ... Full text Link to item Cite

Pepducin ICL1-9-Mediated β2-Adrenergic Receptor-Dependent Cardiomyocyte Contractility Occurs in a Gi Protein/ROCK/PKD-Sensitive Manner.

Journal Article Cardiovasc Drugs Ther · April 2023 PURPOSE: β-Adrenergic receptors (βAR) are essential targets for the treatment of heart failure (HF); however, chronic use of βAR agonists as positive inotropes to increase contractility in a Gs protein-dependent manner is associated with increased mortalit ... Full text Link to item Cite

β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure.

Journal Article Circ Res · March 31, 2023 BACKGROUND: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, β-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs ... Full text Link to item Cite

Work-in-Progress: DIY Ventilator - A CoVID-19 Action

Conference Lecture Notes in Networks and Systems · January 1, 2023 In the Covid-19 pandemic, ventilators became scarce, especially in countries with lower medical standards. A special project has managed to develop a complete ventilator as a kit using cheap parts and 3D printers. In the first two phases of the project a d ... Full text Cite

Ectonucleoside triphosphate diphosphohydrolase-1 (CD39) impacts TGF-β1 responses: insights into cardiac fibrosis and function following myocardial infarction.

Journal Article Am J Physiol Heart Circ Physiol · December 1, 2022 Extracellular purine nucleotides and nucleosides released from activated or injured cells influence multiple aspects of cardiac physiology and pathophysiology. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1; CD39) hydrolyzes released nucleotides ... Full text Link to item Cite

Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics.

Journal Article Basic Res Cardiol · November 29, 2022 Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (β3AR) signaling is beneficial in several forms of HF. Here, we s ... Full text Link to item Cite

Sponging Away Cardiac Injury: A Natural Compound Shows Cardioprotective Promise

Journal Article Jacc Basic to Translational Science · November 1, 2022 Full text Cite

GRK2 in cardiovascular disease and its potential as a therapeutic target.

Journal Article J Mol Cell Cardiol · November 2022 Cardiovascular diseases (CVDs) represent the leading cause of death globally. Despite major advances in the field of pharmacological CVD treatments, particularly in the field of heart failure (HF) research, case numbers and overall mortality remain high an ... Full text Link to item Cite

CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection.

Journal Article Sci Adv · October 21, 2022 Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate t ... Full text Link to item Cite

GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.

Journal Article Blood Adv · August 9, 2022 The critical role of G protein-coupled receptor kinase 2 (GRK2) in regulating cardiac function has been well documented for >3 decades. Targeting GRK2 has therefore been extensively studied as a novel approach to treating cardiovascular disease. However, l ... Full text Link to item Cite

Abstract P3093: Gender-specific Functional Dimorphism Of Bone Marrow Endothelial Progenitor Cells: Estrogen Independent Epigenetic Mechanisms

Conference Circulation Research · August 5, 2022 Introduction: Several studies, including our labs, have previously determined the role of estrogen in augmenting EPC-based cardiac repair; however, a direct comparison of therapeutic efficacy of gende ... Full text Cite

Abstract P3053: Mitochondrial Calcium Accumulation Drives The Progression Of Non-ischemic Heart Failure: Integrated Lessons From Genetic Mouse Models

Conference Circulation Research · August 5, 2022 Acute mitochondrial calcium ( m Ca 2+ ) uptake stimulates bioenergetics to meet increased ATP demand, but when excessive predisposes to necrotic ... Full text Cite

Abstract EC103: A Novel Nuclear Role For REDD1 In Cardiac Insulin Sensitivity And Resistance

Conference Circulation Research · August 5, 2022 Insulin resistance (IR) is a hallmark of type II diabetes (TIID) and causes cardiac dysfunction independent of hypertension and coronary artery disease, or diabetic cardiomyopathy (DC). Impaired metabolism and energetics are a major ca ... Full text Cite

Abstract P2065: Ischemic Injury Aggravated Muscle-specific Mir-499-5p-impaired Angiogenic Property Of Endothelial Cell In Hindlimb Of Diabetic Db/db Mice: Role Of Small Extracellular Vesicles

Conference Circulation Research · August 5, 2022 Background: Recently, skeletal muscle cells (SKMCs) have been reported to be critical for regulation of EC function in limbs. miR-499, a muscle specific microRNA (miR), was found to be modulated in di ... Full text Cite

Abstract P2022: Tipifarnib Mediated Protection By Reduction Of Circulating Exosomes In Pressure Overloaded Cardiac Hypertrophy

Conference Circulation Research · August 5, 2022 Hypertrophic cardiomyopathy (HCM) in response to pathophysiological stress is one of the leading causes of heart failure. A growing body of evidence emphasizes the crucial role of exosomes and their modulated content in aggravating cardiac damage d ... Full text Cite

Abstract P2104: Adeno-associated Virus Serotype 5 Is A Suitable Vector For S100a1-based Gene Therapy Of Post-ischemic Chronic Cardiac Dysfunction

Conference Circulation Research · August 5, 2022 Introduction: For S100A1-based heart failure gene therapies, AAV9 and 6 have shown efficacy in pre-clinical large animal studies. As AAV9 has shown concerning signs of toxicity in clinical studies and ... Full text Cite

Targeting Adiponectin Receptor 1 Phosphorylation Against Ischemic Heart Failure.

Journal Article Circ Res · July 8, 2022 BACKGROUND: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We ... Full text Link to item Cite

Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure.

Journal Article J Mol Cell Cardiol · June 2022 Mitochondrial calcium (mCa2+) uptake couples changes in cardiomyocyte energetic demand to mitochondrial ATP production. However, excessive mCa2+ uptake triggers permeability transition and necrosis. Despite these established roles during acute stress, the ... Full text Open Access Link to item Cite

Mitochondrial GRK2 is a Novel Regulator of Cardiac Energetics

Conference The FASEB Journal · May 2022 G protein‐coupled receptor (GPCR) kinase 2 (GRK2) is highly expressed in the heart, where during injury or heart failure (HF), both its levels and activity increase. GRK2 is canonically studied in the context of GPCR phosphoryl ... Full text Cite

Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels

Journal Article Jacc Basic to Translational Science · April 1, 2022 GRK5’s catalytic activity in regulating basal and stressed cardiac function has not been studied. Herein, we studied knock-in mice in which GRK5 was mutated to render it catalytically inactive (K215R). At baseline, GRK5-K215R mice showed a marked decline i ... Full text Cite

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Journal Article Frontiers in Cellular Neuroscience · March 28, 2022 A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral ther ... Full text Cite

Epidermal growth factor receptor-dependent maintenance of cardiac contractility.

Journal Article Cardiovasc Res · March 25, 2022 AIMS: Epidermal growth factor receptor (EGFR) is essential to the development of multiple tissues and organs and is a target of cancer therapeutics. Due to the embryonic lethality of global EGFR deletion and conflicting reports of cardiac-overexpressed EGF ... Full text Link to item Cite

Cardiomyocyte-GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms.

Journal Article J Cell Physiol · March 2022 Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here, we sought to identify the potential roles of glycogen syn ... Full text Link to item Cite

G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.

Journal Article Cardiovasc Res · January 7, 2022 AIMS: Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy in animal models. However, the rol ... Full text Open Access Link to item Cite

Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function.

Journal Article Circ Res · January 7, 2022 BACKGROUND: Patients with acute myocardial infarction suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of acute myocardial infarction upon adipocyte function is ... Full text Link to item Cite

Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition.

Journal Article Theranostics · 2022 Background and Purpose: Myocardial infarction (MI) in diabetic patients results in higher mortality and morbidity. We and others have previously shown that bone marrow-endothelial progenitor cells (EPCs) promote cardiac neovascularization and attenuate isc ... Full text Open Access Link to item Cite

LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury.

Journal Article Redox Biol · November 2021 RATIONALE: Cell-based therapeutics have been extensively used for cardiac repair yet underperform due to inability of the donated cells to survive in near anoxia after cardiac injury. Cellular metabolism is linked to maintenance of cardiac stem cell (CSC) ... Full text Link to item Cite

Abstract MP247: Mitochondrial Complex V Is Regulated By GRK2 In The Heart

Conference Circulation Research · September 3, 2021 The GPCR kinase GRK2 is highly expressed the heart; importantly, during cardiac injury or heart failure (HF) both levels and activity of GRK2 increase. The role of GRK2 during HF is canonically studied upstream of β-adrenergic desensit ... Full text Cite

Abstract P426: Inactivating Grk5 Impairs Basal Cardiac Function And Survival Via P53 Modulation

Conference Circulation Research · September 3, 2021 Introduction: G protein-coupled receptor (GPCR) kinase 5 (GRK5) is a multifunctional protein and depending on its localization within the cell, it has been shown to elicit either protective or deleter ... Full text Cite

In Vivo Stimulation of α- and β-Adrenoceptors in Mice Differentially Alters Small RNA Content of Circulating Extracellular Vesicles.

Journal Article Cells · May 15, 2021 When myocardial function is compromised as in heart failure (HF), there is activation of the sympathetic nervous system with elevated circulating catecholamine levels. These catecholamines activate cardiac and extra-cardiac adrenergic receptors (ARs). Inte ... Full text Link to item Cite

A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload.

Journal Article J Mol Cell Cardiol · May 2021 G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in ... Full text Open Access Link to item Cite

Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production.

Journal Article Redox Biol · May 2021 BACKGROUND: Mesenchymal stem cell therapy improves ischemic heart failure via incompletely understood mechanisms. C1q-TNFα related protein-9 (CTRP9) is a novel anti-oxidative cardiokine capable of improving the local microenvironment and cell survival by i ... Full text Link to item Cite

Characterization of βARKct engineered cellular extracellular vesicles and model specific cardioprotection.

Journal Article Am J Physiol Heart Circ Physiol · April 1, 2021 Recent data supporting any benefit of stem cell therapy for ischemic heart disease have suggested paracrine-based mechanisms via extracellular vesicles (EVs) including exosomes. We have previously engineered cardiac-derived progenitor cells (CDCs) to expre ... Full text Open Access Link to item Cite

A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure.

Journal Article Sci Signal · March 30, 2021 Aberrant changes in gene expression underlie the pathogenesis and progression of pressure-overload heart failure, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. Signaling through the G protein Gq triggers m ... Full text Open Access Link to item Cite

Metabolomics, heart disease and aging.

Journal Article Aging (Albany NY) · March 10, 2021 Full text Link to item Cite

Targeting GRK5 for Treating Chronic Degenerative Diseases.

Journal Article Int J Mol Sci · February 15, 2021 G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and they are responsible for the transduction of extracellular signals, regulating almost all aspects of mammalian physiology. These receptors are specifically regulated b ... Full text Link to item Cite

KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy.

Journal Article Circ Res · February 5, 2021 RATIONALE: Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that type-1 diabetes is associated with increa ... Full text Link to item Cite

GRK5 is a regulator of fibroblast activation and cardiac fibrosis.

Journal Article Proc Natl Acad Sci U S A · February 2, 2021 Pathological remodeling of the heart is a hallmark of chronic heart failure (HF) and these structural changes further perpetuate the disease. Cardiac fibroblasts are the critical cell type that is responsible for maintaining the structural integrity of the ... Full text Link to item Cite

Nitric Oxide and S-Nitrosylation in Cardiac Regulation: G Protein-Coupled Receptor Kinase-2 and β-Arrestins as Targets.

Journal Article Int J Mol Sci · January 7, 2021 Cardiac diseases including heart failure (HF), are the leading cause of morbidity and mortality globally. Among the prominent characteristics of HF is the loss of β-adrenoceptor (AR)-mediated inotropic reserve. This is primarily due to the derangements in ... Full text Link to item Cite

MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis.

Journal Article Front Immunol · 2021 Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. ... Full text Open Access Link to item Cite

Effects of myocardial ischemia/reperfusion injury on plasma metabolomic profile during aging.

Journal Article Aging Cell · January 2021 BACKGROUND: Heart disease is a frequent cause of hospitalization and mortality for elderly patients. A common feature of both heart disease and aging itself is the involvement of metabolic organ alterations ultimately leading to changes in circulating meta ... Full text Link to item Cite

GRK5 controls basal cardiac function and survival via direct p53 modulation

Conference EUROPEAN JOURNAL OF HEART FAILURE · 2021 Cite

Gender differences in β3-adrenoceptor-mediated cardiac remodeling

Conference BRITISH JOURNAL OF PHARMACOLOGY · 2021 Cite

Constructing and evaluating caspase-activatable adeno-associated virus vector for gene delivery to the injured heart.

Journal Article J Control Release · December 10, 2020 Adeno-associated virus (AAV) is a promising vector for gene therapy, but its broad tropism can be detrimental if the transgene being delivered is harmful when expressed ubiquitously in the body, i.e. in non-target tissues. Delivering the transgene of inter ... Full text Link to item Cite

Identification and Comparison of Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different Mouse Stem Cells.

Journal Article Cells · September 15, 2020 Extracellular vesicles (EVs) derived from stem /progenitor cells harbor immense potential to promote cardiomyocyte survival and neovascularization, and to mitigate ischemic injury. However, EVs' parental stem/progenitor cells showed modest benefits in clin ... Full text Link to item Cite

Genomic Binding Patterns of Forkhead Box Protein O1 Reveal Its Unique Role in Cardiac Hypertrophy.

Journal Article Circulation · September 2020 BACKGROUND: Cardiac hypertrophic growth is mediated by robust changes in gene expression and changes that underlie the increase in cardiomyocyte size. The former is regulated by RNA polymerase II (pol II) de novo recruitment or loss; the latter involves in ... Full text Open Access Link to item Cite

Abstract 249: Plasma Exosomes Impair Angiogenesis in Ischemic Hind Limb of Diabetic Mice- Role of Histone Methylation

Conference Circulation Research · July 31, 2020 Background: Critical limb ischemia (CLI) is one of most prevenient cardiovascular disease in diabetic patients. Recent evidence suggests that altered cargo and function of plasma exosomes (plasma-Exo) ... Full text Cite

Abstract 381: Mcur1 is a Potential Target to Modulate Cardiac Contractility and Alleviate Cardiac Function During Heart Failure

Conference Circulation Research · July 31, 2020 Cardiac contractility is regulated by the intracellular Ca 2+ concentration fluxes which are actively regulated by multiple channels and transporters. Ca 2+ ... Full text Cite

Abstract 340: Myocyte-borne Bdnf is Essential to Limit Post-ischemic Cardiac Injury and Dysfunction

Conference Circulation Research · July 31, 2020 Brain-derived neurotrophic factor (BDNF)/ tyrosine receptor kinase B (TrkB) signaling is essential for normal cardiac contraction/relaxation. Alt ... Full text Cite

Abstract MP122: Effects of Cardiac Beta3-Adrenoceptors on the Inhibition of G Protein-coupled Receptor Kinase 2 via S-nitrosylation

Conference Circulation Research · July 31, 2020 G Protein-Coupled Receptor Kinase 2 (GRK2) is a culprit in the loss of cardiac contractile function in heart failure due to β-Adrenoceptor (AR) desensitization after its upregulation. Indeed, its inhibition has been demonstrated to improve cardiac ... Full text Cite

Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging.

Journal Article Am J Physiol Heart Circ Physiol · May 1, 2020 Nitric oxide (NO) and S-nitrosothiol (SNO) are considered cardio- and vasoprotective substances. We now understand that one mechanism in which NO/SNOs provide cardiovascular protection is through their direct inhibition of cardiac G protein-coupled recepto ... Full text Open Access Link to item Cite

Author Correction: Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis.

Journal Article Nat Commun · May 1, 2020 An amendment to this paper has been published and can be accessed via a link at the top of the paper. ... Full text Link to item Cite

B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension.

Journal Article JCI Insight · April 23, 2020 B-type natriuretic peptide (BNP) is secreted by ventricular cardiomyocytes in response to various types of cardiac stress and has been used as a heart failure marker. In septic patients, increased BNP suggests poor prognosis; however, no causal link has be ... Full text Link to item Cite

Small Extracellular Microvesicles Mediated Pathological Communications Between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanism Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice.

Journal Article Circulation · March 24, 2020 BACKGROUND: Diabetes mellitus exacerbates myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Adipocyte dysfunction contributes to remote organ injury. However, the molecular mechanisms linking dysfunctional adipocytes to i ... Full text Link to item Cite

Interleukin-10 Deficiency Alters Endothelial Progenitor Cell-Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment.

Journal Article Circ Res · January 31, 2020 Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Obje ... Full text Open Access Link to item Cite

Metabolic crosstalk between the heart and fat

Journal Article Korean Circulation Journal · January 1, 2020 It is now recognized that the heart can behave as a true endocrine organ, which can modulate the function of other tissues. Emerging evidence has shown that visceral fat is one such distant organ the heart communicates with. In fact, it appears that bi-dir ... Full text Cite

G protein-coupled receptor kinases as therapeutic targets in the heart.

Journal Article Nat Rev Cardiol · October 2019 G protein-coupled receptors (GPCRs) are critical cellular sensors that mediate numerous physiological processes. In the heart, multiple GPCRs are expressed on various cell types, where they coordinate to regulate cardiac function by modulating critical pro ... Full text Link to item Cite

Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis.

Journal Article Nat Commun · September 20, 2019 Circular RNAs are generated from many protein-coding genes, but their role in cardiovascular health and disease states remains unknown. Here we report identification of circRNA transcripts that are differentially expressed in post myocardial infarction (MI ... Full text Link to item Cite

Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction

Conference Jci Insight · August 8, 2019 Podoplanin (PDPN), a small mucin-type transmembrane glycoprotein, has been recently shown to be expressed by lymphangiogenic, fibrogenic, and mesenchymal progenitor cells in the acutely and chronically infarcted myocardium. PDPN binds to a C-type lectin–li ... Full text Cite

Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe.

Journal Article Proc Natl Acad Sci U S A · August 6, 2019 G protein-coupled receptor (GPCR) kinases (GRKs) are responsible for initiating desensitization of activated GPCRs. GRK5 is potently inhibited by the calcium-sensing protein calmodulin (CaM), which leads to nuclear translocation of GRK5 and promotion of ca ... Full text Link to item Cite

Podoplanin neutralization improves cardiac remodeling and function after acute myocardial infarction.

Journal Article JCI Insight · July 9, 2019 Podoplanin, a small mucine-type transmembrane glycoprotein, has been recently shown to be expressed by lymphangiogenic, fibrogenic and mesenchymal progenitor cells in the acutely and chronically infarcted myocardium. Podoplanin binds to CLEC-2, a C-type le ... Full text Open Access Link to item Cite

Transient Introduction of miR-294 in the Heart Promotes Cardiomyocyte Cell Cycle Reentry After Injury.

Journal Article Circ Res · June 21, 2019 RATIONALE: Embryonic heart is characterized of rapidly dividing cardiomyocytes required to build a working myocardium. Cardiomyocytes retain some proliferative capacity in the neonates but lose it in adulthood. Consequently, a number of signaling hubs incl ... Full text Link to item Cite

Myocardial Strain and Cardiac Output are Preferable Measurements for Cardiac Dysfunction and Can Predict Mortality in Septic Mice.

Journal Article J Am Heart Assoc · May 21, 2019 Background Sepsis is the overwhelming host response to infection leading to shock and multiple organ dysfunction. Cardiovascular complications greatly increase sepsis-associated mortality. Although murine models are routinely used for preclinical studies, ... Full text Open Access Link to item Cite

Yap/Taz regulate alveolar regeneration and resolution of lung inflammation.

Journal Article J Clin Invest · April 15, 2019 Alveolar epithelium plays a pivotal role in protecting the lungs from inhaled infectious agents. Therefore, the regenerative capacity of the alveolar epithelium is critical for recovery from these insults in order to rebuild the epithelial barrier and rest ... Full text Link to item Cite

Alteration of myocardial GRK2 produces a global metabolic phenotype.

Journal Article JCI Insight · April 4, 2019 A vast body of literature has established GRK2 as a key player in the development and progression of heart failure. Inhibition of GRK2 improves cardiac function post injury in numerous animal models. In recent years, discovery of several non-canonical GRK2 ... Full text Link to item Cite

Prior β-blocker treatment decreases leukocyte responsiveness to injury.

Journal Article JCI Insight · March 28, 2019 Following injury, leukocytes are released from hematopoietic organs and migrate to the site of damage to regulate tissue inflammation and repair, however leukocytes lacking β2-adrenergic receptor (β2AR) expression have marked impairments in these processes ... Full text Link to item Cite

Echocardiographic Strain Analysis for the Early Detection of Left Ventricular Systolic/Diastolic Dysfunction and Dyssynchrony in a Mouse Model of Physiological Aging.

Journal Article J Gerontol A Biol Sci Med Sci · March 14, 2019 Heart disease is the leading cause of hospitalization and death worldwide, severely affecting health care costs. Aging is a significant risk factor for heart disease, and the senescent heart is characterized by structural and functional changes including d ... Full text Link to item Cite

Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury.

Journal Article Mol Ther · March 6, 2019 Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this ... Full text Link to item Cite

Sympathetic nervous system in age-related cardiovascular dysfunction: Pathophysiology and therapeutic perspective.

Journal Article Int J Biochem Cell Biol · March 2019 Cardiovascular diseases such as heart failure and metabolic syndrome have high prevalence in the elderly population and are leading causes of death, disability, hospitalization, driving high healthcare costs worldwide. To reduce this social and economic bu ... Full text Link to item Cite

GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy.

Journal Article Expert Opin Ther Targets · March 2019 One in every four deaths in the United States is attributed to cardiovascular disease, hence the development and employment of novel and effective therapeutics are necessary to improve the quality of life and survival of affected patient. Pathological hype ... Full text Link to item Cite

Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice.

Journal Article Neuromuscul Disord · March 2019 So far effective strategies to treat cardiomyopathy in patients with muscular dystrophies are still not clearly defined. Previously, treatment with β-blockers showed beneficial effects on the development of cardiomyopathy in dystrophin-deficient (mdx) mice ... Full text Link to item Cite

Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction

Journal Article Jacc Basic to Translational Science · February 1, 2019 Myocardial infarction (MI)−induced cardiac fibrosis attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Expression of connective tissue growth factor (CTGF) is elevated in affected organs in virtually every fib ... Full text Cite

Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy.

Journal Article J Mol Cell Cardiol · February 2019 Sepsis is the overwhelming systemic immune response to infection, which can result in multiple organ dysfunction and septic shock. Myocardial dysfunction during sepsis is associated with advanced disease and significantly increased in-hospital mortality. O ... Full text Link to item Cite

Expression of Concern: Increasing cardiac contractility after myocardial infarction exacerbates cardiac injury and pump dysfunction (Circulation Research (2010) 107 (800-809) DOI: 10.1161/CIRCRESAHA.110.219220)

Journal Article Circulation Research · January 18, 2019 Harvard Medical School and Brigham and Women's Hospital (BWH) have notified the American Heart Association that they have completed a review into concerns about the integrity of certain data generated in a former laboratory at BWH. The review concluded tha ... Full text Cite

Convergences of Life Sciences and Engineering in Understanding and Treating Heart Failure.

Journal Article Circ Res · January 4, 2019 On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance t ... Full text Link to item Cite

Aldosterone Jeopardizes Myocardial Insulin and β-Adrenergic Receptor Signaling via G Protein-Coupled Receptor Kinase 2

Journal Article Frontiers in Pharmacology · January 1, 2019 Hyperaldosteronism alters cardiac function, inducing adverse left ventricle (LV) remodeling either via increased fibrosis deposition, mitochondrial dysfunction, or both. These harmful effects are due, at least in part, to the activation of the G protein-co ... Full text Cite

Aldosterone and Myocardial Pathology.

Chapter · 2019 Aldosterone (Aldo) has been intensively studied for years since its isolation by Simpson and Tait in the 1950s. Interestingly, although most early research around Aldo's actions focused primarily on its interaction with the kidney, it was soon evident that ... Full text Link to item Cite

Ethyl Pyruvate Modulates Murine Dendritic Cell Activation and Survival Through Their Immunometabolism.

Journal Article Front Immunol · 2019 Attenuating the innate immunity activation could ameliorate inflammation and disease in settings such as transplant rejection or autoimmunity. Recently, a pivotal role for metabolic re-programming in TLR-induced dendritic cell (DC) activation has emerged. ... Full text Link to item Cite

Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation.

Journal Article Sci Signal · December 11, 2018 Increased abundance of GRK2 [G protein-coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In ... Full text Open Access Link to item Cite

G protein-coupled receptor kinase 2 contributes to impaired fatty acid metabolism in the failing heart.

Journal Article J Mol Cell Cardiol · October 2018 Increased G protein-coupled receptor kinase (GRK)2 is central to heart failure (HF) pathogenesis, via desensitization of β-adrenergic receptors and loss of contractile reserve. Since GRK2 has been shown to compromise fatty acid (FA) oxidation, this kinase ... Full text Link to item Cite

Abstract 580: A β-arrestin-Biased β2-Adrenergic Receptor-Specific Pepducin Confers Cardioprotection

Conference Circulation Research · August 3, 2018 Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the fir ... Full text Cite

Abstract 578: β-arrestin-Biased β2-Adrenergic Receptor Signaling Enhances Cardiomyocyte Contractility via ROCK-Dependent Signaling

Conference Circulation Research · August 3, 2018 During heart failure, chronically decreased cardiac output can be treated with positive inotropes, but classic inotropes such as β-adrenergic receptor (βAR) agonists that increase cAMP-dependent Ca 2+ ... Full text Cite

Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function

Conference Circulation Research · August 3, 2018 Cardiac contractility is regulated by the intracellular Ca 2+ concentration fluxes which are maintained by multiple channels and transporters. Mitochondrial Calcium Uniporter (MCU) is the hi ... Full text Cite

Abstract 333: TNF Receptor Modulation of Progenitor Cells and Exosomes for Myocardial Repair

Conference Circulation Research · August 3, 2018 Our published studies, using TNFR1 and TNFR2 knockout (KO) mice have demonstrated that negative effects of TNF during ischemic tissue repair including enhanced apoptosis and inflammatory cytokines expression and signaling, is largely mediated by TN ... Full text Cite

Abstract 557: Exosome Biogenesis/Uptake Mediates Cardioprotection by Globular Adiponectin but Not High Molecular Weight Adiponectin

Conference Circulation Research · August 3, 2018 Objectives: Adiponectin, a multifunction adipokine with established cardioprotective effect, presents in high molecular weight (HMW) and globular isotype (gAPN). Recent study demonstrated that HMW car ... Full text Cite

Abstract 288: Circular RNA CircFNDC3b Modulates Cardiac Repair After Myocardial Infarction via FUS-1/VEGF-A Axis

Conference Circulation Research · August 3, 2018 Circular RNA (circRNA) is a new addition to the list of growing body of non-coding RNAs.Recent studies highlighted that circRNA are dysregulated in cardiovascular disease. However,knowledge of the role of circRNAs in ischemic cardiac injury is limi ... Full text Cite

Abstract 262: GRK5 is a Novel Regulator of Fibroblast Activation

Conference Circulation Research · August 3, 2018 Pathological remodeling of the heart is a hallmark of heart failure (HF) and these structural changes of the heart further perpetuates the disease. Cardiac fibroblasts are the critical cell type that is responsible for maintaining the ... Full text Cite

Abstract 312: Cardiomyocyte-secreted Signaling Factors Modulate Adipocyte Differentiation And Function

Conference Circulation Research · August 3, 2018 Heart failure (HF) alters cardiomyocyte metabolism by altering energy substrate utilization and mitochondrial function, which has potential implications for global metabolic health. Recent studies demonstrated that cardiomyocyte-released signaling ... Full text Cite

Abstract 109: G Protein-coupled Receptor Kinase 2 Impairs Fatty Acid Metabolism in the Failing Heart Through Novel Mechanisms

Conference Circulation Research · August 3, 2018 Compromised contractility and energetics are hallmarks of the failing heart. Increased G protein-coupled receptor kinase (GRK)2 is central to the pathogenesis of heart failure (HF), via desensitization of beta-adrenergic receptors and, ... Full text Cite

Abstract 220: Adipocyte-Derived Exosome-Containing miRNAs Exacerbated Cardiac Ischemia/Reperfusion Injury in Diabetic Mice

Conference Circulation Research · August 3, 2018 Objective: Diabetes significantly exacerbates myocardial ischemia/reperfusion (MI/R) injury. However, the molecules mediate the crosstalk between adipose tissue and heart is unclear. The current study ... Full text Cite

Abstract 318: MicroRNA Regulation of G Protein-Coupled Receptor Kinase 2 After Cardiac Injury

Conference Circulation Research · August 3, 2018 The increase in myocardial expression and activity of G Protein-Coupled Receptor (GPCR) Kinase 2 (GRK2) during the development and progression of heart failure (HF) has been documented to be pathological. Upregulation of GRK2 that is involved with ... Full text Cite

Abstract 292: Mitochondrial CLIC4 and CLIC5B Mediate Cardio-protection From Ischemia/reperfusion Injury

Conference Circulation Research · August 3, 2018 Mitochondria are important for regulating myocardial physiology, cardiac function and cardio-protection from ischemia/reperfusion injury (IR). Cation channels like BK Ca and K Full text Cite

Designer Approaches for G Protein–Coupled Receptor Modulation for Cardiovascular Disease

Journal Article Jacc Basic to Translational Science · August 1, 2018 The new horizon for cardiac therapy may lie beneath the surface, with the downstream mediators of G protein–coupled receptor (GPCR) activity. Targeted approaches have shown that receptor activation may be biased toward signaling through G proteins or throu ... Full text Cite

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration.

Journal Article J Biol Chem · July 13, 2018 SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphami ... Full text Link to item Cite

PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulates G-protein-coupled receptor kinase 5 (GRK5)-induced cardiac hypertrophy in vitro.

Journal Article J Biol Chem · May 25, 2018 PH domain leucine-rich repeat protein phosphatase (PHLPP) is a serine/threonine phosphatase that has been shown to regulate cell growth and survival through dephosphorylation of several members of the AGC family of kinases. G-protein-coupled receptor kinas ... Full text Link to item Cite

S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence.

Journal Article Mol Cell · May 3, 2018 Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and β-arrestins (βarr1 and βarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis βarr-mediated transduction, endogenous mechanisms for b ... Full text Link to item Cite

β-arrestin2 affects cardiac progenitor cell survival through cell mobility and tube formation in severe hypoxia

Journal Article Korean Circulation Journal · April 1, 2018 Background and Objectives: β-arrestin2 (β-arr2) basically regulates multiple signaling pathways in mammalian cells by desensitization and internalization of G-protein coupled receptors (GPCRs). We investigated impacts of β-arr2 on survival, mobility, and t ... Full text Cite

Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure.

Journal Article Circ Heart Fail · March 2018 BACKGROUND: Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans. Chronic ischemic heart failure (HF) is associated with reduced cardiac sympathetic innervation, dysfunctio ... Full text Open Access Link to item Cite

Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling.

Journal Article Theranostics · 2018 Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thu ... Full text Link to item Cite

New Insights in Cardiac β-Adrenergic Signaling During Heart Failure and Aging.

Journal Article Front Pharmacol · 2018 Heart failure (HF) has become increasingly common within the elderly population, decreasing their survival and overall quality of life. In fact, despite the improvements in treatment, many elderly people suffer from cardiac dysfunction (HF, valvular diseas ... Full text Link to item Cite

GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease.

Journal Article Cell Signal · January 2018 Nitric oxide (NO), initially identified as endothelium-derived relaxing factor (EDRF), is a gaso-transmitter with important regulatory roles in the cardiovascular, nervous and immune systems. In the former, this diatomic molecule and free radical gas contr ... Full text Link to item Cite

Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors.

Journal Article Mol Pharmacol · December 2017 G protein-coupled receptor kinases (GRKs) phosphorylate activated receptors to promote arrestin binding, decoupling from heterotrimeric G proteins, and internalization. GRK2 and GRK5 are overexpressed in the failing heart and thus have become therapeutic t ... Full text Link to item Cite

C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways.

Journal Article Circulation · November 28, 2017 BACKGROUND: Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair after myocardial infarction. CTR ... Full text Open Access Link to item Cite

β-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes.

Journal Article Hypertension · November 2017 Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins βarr (β-arrestin)-1 and βarr-2 are functionally distinct in the heart. βarr1 is cardiotox ... Full text Link to item Cite

Impact of paroxetine on proximal β-adrenergic receptor signaling.

Journal Article Cell Signal · October 2017 β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has long been recognized as a maladaptive process in the progression of various disease states. T ... Full text Link to item Cite

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling.

Journal Article JCI Insight · September 7, 2017 The oncoprotein Mdm2 is a RING domain-containing E3 ubiquitin ligase that ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, thereby regulating β-adrenergic receptor (βAR) signaling and endocytosis. Previous studies showed that cardi ... Full text Open Access Link to item Cite

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium.

Journal Article Circulation · September 5, 2017 BACKGROUND: Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast pr ... Full text Link to item Cite

Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling.

Journal Article J Cardiovasc Pharmacol · September 2017 G protein-coupled receptor kinases (GRKs) are classically known for their role in regulating the activity of the largest known class of membrane receptors, which influence diverse biological processes in every cell type in the human body. As researchers ha ... Full text Link to item Cite

β1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via β3AR-Dependent Protective Sphingosine-1 Phosphate Signaling.

Journal Article J Am Coll Cardiol · July 11, 2017 BACKGROUND: Although β-blockers increase survival in patients with heart failure (HF), the mechanisms behind this protection are not fully understood, and not all patients with HF respond favorably to them. We recently showed that, in cardiomyocytes, a rec ... Full text Link to item Cite

Therapeutic inhibition of miR-375 attenuates post-myocardial infarction inflammatory response and left ventricular dysfunction via PDK-1-AKT signalling axis.

Journal Article Cardiovasc Res · July 1, 2017 AIMS: Increased miR-375 levels has been implicated in rodent models of myocardial infarction (MI) and with patients with heart failure. However, no prior study had established a therapeutic role of miR-375 in ischemic myocardium. Therefore, we assessed whe ... Full text Link to item Cite

Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.

Journal Article J Med Chem · April 13, 2017 In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart, making them de ... Full text Link to item Cite

Targeting β3-Adrenergic Receptors in the Heart: Selective Agonism and β-Blockade.

Journal Article J Cardiovasc Pharmacol · February 2017 Cardiac diseases, such as heart failure, remain leading causes of morbidity and mortality worldwide, with myocardial infarction as the most common etiology. HF is characterized by β-adrenergic receptor (βAR) dysregulation that is primarily due to the upreg ... Full text Link to item Cite

Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity.

Journal Article Proc Natl Acad Sci U S A · January 31, 2017 Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardiomyocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction ... Full text Link to item Cite

Sphingosine Kinases and Sphingosine 1-Phosphate Receptors: Signaling and Actions in the Cardiovascular System.

Journal Article Front Pharmacol · 2017 The sphingosine kinases 1 and 2 (SphK1 and 2) catalyze the phosphorylation of the lipid, sphingosine, generating the signal transmitter, sphingosine 1-phosphate (S1P). The activation of such kinases and the subsequent S1P generation and secretion in the bl ... Full text Link to item Cite

microRNA in Cardiovascular Aging and Age-Related Cardiovascular Diseases.

Journal Article Front Med (Lausanne) · 2017 Over the last decades, life expectancy has significantly increased although several chronic diseases persist in the population, with aging as the leading risk factor. Despite improvements in diagnosis and treatment, many elderlies suffer from cardiovascula ... Full text Link to item Cite

Restoring diabetes-induced autophagic flux arrest in ischemic/reperfused heart by ADIPOR (adiponectin receptor) activation involves both AMPK-dependent and AMPK-independent signaling.

Journal Article Autophagy · 2017 Macroautophagy/autophagy is increasingly recognized as an important regulator of myocardial ischemia-reperfusion (MI-R) injury. However, whether and how diabetes may alter autophagy in response to MI-R remains unknown. Deficiency of ADIPOQ, a cardioprotect ... Full text Open Access Link to item Cite

G protein-coupled receptor kinase 2 promotes cardiac hypertrophy.

Journal Article PLoS One · 2017 The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal ... Full text Link to item Cite

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury.

Journal Article Proc Natl Acad Sci U S A · December 27, 2016 Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of β2-adrenergic receptors (β2ARs) in the regulation of immune cell localization following ac ... Full text Link to item Cite

Cardiac Fibroblast GRK2 Deletion Enhances Contractility and Remodeling Following Ischemia/Reperfusion Injury.

Journal Article Circ Res · October 28, 2016 RATIONALE: G protein-coupled receptor kinase 2 (GRK2) is an important molecule upregulated after myocardial injury and during heart failure. Myocyte-specific GRK2 loss before and after myocardial ischemic injury improves cardiac function and remodeling. Th ... Full text Link to item Cite

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy.

Journal Article J Biol Chem · October 14, 2016 GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 ... Full text Link to item Cite

The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development.

Journal Article Pharmacol Res · August 2016 Heart failure (HF) is a global epidemic with the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) are prominent regulators of cardiovascular function. Activated GPCRs are "turned off" by GPCR k ... Full text Link to item Cite

Leukocyte-Expressed β2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury.

Journal Article Circulation · July 12, 2016 BACKGROUND: Immune cell-mediated inflammation is an essential process for mounting a repair response after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune system function through β-adrenergic receptors (βARs); however ... Full text Link to item Cite

β-arrestin-biased signaling through the β2-adrenergic receptor promotes cardiomyocyte contraction.

Journal Article Proc Natl Acad Sci U S A · July 12, 2016 β-adrenergic receptors (βARs) are critical regulators of acute cardiovascular physiology. In response to elevated catecholamine stimulation during development of congestive heart failure (CHF), chronic activation of Gs-dependent β1AR and Gi-dependent β2AR ... Full text Link to item Cite

Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation.

Journal Article Arterioscler Thromb Vasc Biol · June 2016 OBJECTIVE: Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activa ... Full text Link to item Cite

MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics.

Journal Article Cell Rep · May 24, 2016 Mitochondrial Ca(2+) Uniporter (MCU)-dependent mitochondrial Ca(2+) uptake is the primary mechanism for increasing matrix Ca(2+) in most cell types. However, a limited understanding of the MCU complex assembly impedes the comprehension of the precise mecha ... Full text Link to item Cite

Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors.

Journal Article J Med Chem · April 28, 2016 G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associate ... Full text Link to item Cite

Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy.

Journal Article Circ Res · April 15, 2016 RATIONALE: Cardiac myocyte-specific deletion of either glycogen synthase kinase (GSK)-3α and GSK-3β leads to cardiac protection after myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important ... Full text Link to item Cite

Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure.

Journal Article Circ Res · April 1, 2016 RATIONALE: Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-couple ... Full text Link to item Cite

Structure–activity relationship study of angiotensin II analogs in terms of β-arrestin-dependent signaling to aldosterone production

Journal Article Pharmacology Research and Perspectives · April 1, 2016 The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion induction, a steroid hormone that contributes to the pathology of postmyocardial infarction (MI) heart failure (HF), is mediated by both Gq/11 proteins ... Full text Cite

A peptide of the RGS domain of GRK2 binds and inhibits Gα(q) to suppress pathological cardiac hypertrophy and dysfunction.

Journal Article Sci Signal · March 22, 2016 G protein-coupled receptor (GPCR) kinases (GRKs) play a critical role in cardiac function by regulating GPCR activity. GRK2 suppresses GPCR signaling by phosphorylating and desensitizing active GPCRs, and through protein-protein interactions that uncouple ... Full text Link to item Cite

Science Signaling Podcast for 22 March 2016: Preventing heart failure with GRK2

Journal Article Science Signaling · March 22, 2016 This Podcast features an interview with Sarah Schumacher and Walter Koch, authors of a Research Article that appears in the 22 March 2016 issue of Science Signaling, about a peptide that can inhibit pathological cardiac hypertrophy in mice. Untreated or po ... Full text Cite

c-kit+ Cardiac Stem Cells: Spontaneous Creation or a Perplexing Reality.

Journal Article Circ Res · March 4, 2016 One of the lingering controversies in the field of cardiac regenerative medicine has been around the origin of c-kit+ cardiac stem cells in the heart and their contribution towards cardiac homeostasis. A recent study reports that a subpopulation of c-kit+ ... Full text Link to item Cite

Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases.

Journal Article Nat Commun · March 2, 2016 Hyper-aldosteronism is associated with myocardial dysfunction including induction of cardiac fibrosis and maladaptive hypertrophy. Mechanisms of these cardiotoxicities are not fully understood. Here we show that mineralocorticoid receptor (MR) activation b ... Full text Link to item Cite

"Canonical and non-canonical actions of GRK5 in the heart".

Journal Article J Mol Cell Cardiol · March 2016 As the average world-wide lifespan continues to increase, heart failure (HF) has dramatically increased in incidence leading to the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) play a promi ... Full text Link to item Cite

BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes.

Journal Article J Mol Cell Cardiol · March 2016 Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 lev ... Full text Link to item Cite

β Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves β2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia.

Journal Article J Pharmacol Exp Ther · February 2016 After hindlimb ischemia (HI), increased catecholamine levels within the ischemic muscle can cause dysregulation of β2-adrenergic receptor (β2AR) signaling, leading to reduced revascularization. Indeed, in vivo β2AR overexpression via gene therapy enhances ... Full text Link to item Cite

G-Protein-Coupled Receptors and Their Kinases in Cardiac Regulation

Chapter · January 1, 2016 The superfamily of G-protein-coupled receptors (GPCRs), or seven transmembrane-spanning receptors (7TMRs), represents the largest family of membrane proteins that transduce cell signals via heterotrimeric G proteins from neurohormones, ions, and sensory st ... Full text Cite

Vasopressin type 1A receptor deletion enhances cardiac contractility, β-adrenergic receptor sensitivity and acute cardiac injury-induced dysfunction

Journal Article Clinical Science · January 1, 2016 Vasopressin type 1A receptor (V1AR) expression is elevated in chronic human heart failure (HF) and contributes to cardiac dysfunction in animal models, in part via reduced β-adrenergic receptor (βAR) responsiveness. Although cardiac V1AR overexpression and ... Full text Cite

β-arrestin-biased signaling through the β2-adrenergic receptor promotes cardiomyocyte contraction

Journal Article PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA · 2016 Full text Cite

Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias.

Journal Article Basic Res Cardiol · January 2016 Persistent elevation of Ca(2+) influx due to prolongation of the action potential (AP), chronic activation of the β-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca(2+) influx are usually linked to prolonge ... Full text Link to item Cite

Eating Away at Heart Failure.

Journal Article J Am Coll Cardiol · December 8, 2015 Full text Link to item Cite

Differential Role of G Protein-Coupled Receptor Kinase 5 in Physiological Versus Pathological Cardiac Hypertrophy.

Journal Article Circ Res · December 4, 2015 RATIONALE: G protein-coupled receptor kinases (GRKs) are dynamic regulators of cellular signaling. GRK5 is highly expressed within myocardium and is upregulated in heart failure. Although GRK5 is a critical regulator of cardiac G protein-coupled receptor s ... Full text Link to item Cite

Interleukin-10 inhibits chronic angiotensin II-induced pathological autophagy.

Journal Article J Mol Cell Cardiol · December 2015 BACKGROUND: Although autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be im ... Full text Link to item Cite

GRK2 compromises cardiomyocyte mitochondrial function by diminishing fatty acid-mediated oxygen consumption and increasing superoxide levels.

Journal Article J Mol Cell Cardiol · December 2015 The G protein-coupled receptor kinase-2 (GRK2) is upregulated in the injured heart and contributes to heart failure pathogenesis. GRK2 was recently shown to associate with mitochondria but its functional impact in myocytes due to this localization is uncle ... Full text Link to item Cite

Negative Regulation of miR-375 by Interleukin-10 Enhances Bone Marrow-Derived Progenitor Cell-Mediated Myocardial Repair and Function After Myocardial Infarction.

Journal Article Stem Cells · December 2015 Poor survival and function of transplanted cells in ischemic and inflamed myocardium likely compromises the functional benefit of stem cell-based therapies. We have earlier reported that co-administration of interleukin (IL)-10 and BMPAC enhances cell surv ... Full text Link to item Cite

Walter J. Koch

Journal Article Circulation Research · November 6, 2015 Full text Cite

Cardiac-specific disruption of Bin1 in mice enables a model of stress- and age-associated dilated cardiomyopathy.

Journal Article J Cell Biochem · November 2015 Non-compensated dilated cardiomyopathy (DCM) leading to death from heart failure is rising rapidly in developed countries due to aging demographics, and there is a need for informative preclinical models to guide the development of effective therapeutic st ... Full text Link to item Cite

SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.

Journal Article Mol Cell · October 1, 2015 Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic can ... Full text Link to item Cite

Comparative effects of urocortins and stresscopin on cardiac myocyte contractility.

Journal Article J Mol Cell Cardiol · September 2015 RATIONALE: There is a current need for the development of new therapies for patients with heart failure. OBJECTIVE: We test the effects of members of the corticotropin-releasing factor (CRF) family of peptides on myocyte contractility to validate them as p ... Full text Link to item Cite

Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor.

Journal Article J Biol Chem · August 21, 2015 G protein-coupled receptor kinases (GRKs) regulate cell signaling by initiating the desensitization of active G protein-coupled receptors. The two most widely expressed GRKs (GRK2 and GRK5) play a role in cardiovascular disease and thus represent important ... Full text Link to item Cite

Cardiac Dysfunction in HIV-1 Transgenic Mouse: Role of Stress and BAG3.

Journal Article Clin Transl Sci · August 2015 Since highly active antiretroviral therapy improved long-term survival of acquired immunodeficiency syndrome (AIDS) patients, AIDS cardiomyopathy has become an increasingly relevant clinical problem. We used human immunodeficiency virus (HIV)-1 transgenic ... Full text Link to item Cite

S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction.

Journal Article Mol Ther · August 2015 Restoring expression levels of the EF-hand calcium (Ca(2+)) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca(2+) handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca(2+) resequestration ... Full text Link to item Cite

AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings.

Journal Article Am J Physiol Endocrinol Metab · August 1, 2015 Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The curre ... Full text Link to item Cite

The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition.

Journal Article Cell Rep · July 7, 2015 Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca(2+)), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyt ... Full text Link to item Cite

Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction.

Journal Article Circ Res · June 19, 2015 RATIONALE: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to various concerns. Recently, salutary effects of stem cells have been connected to exosome secretion. ESCs have the ability to produce exosomes, howeve ... Full text Link to item Cite

Consequence of the tumor-associated conversion to cyclin D1b.

Journal Article EMBO Mol Med · May 2015 Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to c ... Full text Link to item Cite

G-protein-coupled receptor kinase 2-mediated desensitization of adiponectin receptor 1 in failing heart.

Journal Article Circulation · April 21, 2015 BACKGROUND: Phosphorylative desensitization of G-protein-coupled receptors contributes significantly to post-myocardial infarction (MI) remodeling and heart failure (HF). Here, we determined whether adiponectin receptors (AdipoRs) 1 and 2 (the 7-transmembr ... Full text Link to item Cite

The evolving impact of g protein-coupled receptor kinases in cardiac health and disease.

Journal Article Physiol Rev · April 2015 G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including p ... Full text Link to item Cite

A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice.

Journal Article Sci Transl Med · March 18, 2015 In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. We show that the microRNA cluster miR302-367 is important for cardiomyocyte prolif ... Full text Link to item Cite

Ca²⁺ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance.

Journal Article Am J Physiol Heart Circ Physiol · March 15, 2015 Ubiquitously expressed Trpm2 channel limits oxidative stress and preserves mitochondrial function. We first demonstrated that intracellular Ca(2+) concentration increase after Trpm2 activation was due to direct Ca(2+) influx and not indirectly via reverse ... Full text Link to item Cite

Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction.

Journal Article Sci Transl Med · March 4, 2015 Heart failure (HF) is a disease of epidemic proportion and is associated with exceedingly high health care costs. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) kinase 2 (GRK2), which is up-regulated in the failing hu ... Full text Link to item Cite

Temporal and gefitinib-sensitive regulation of cardiac cytokine expression via chronic β-adrenergic receptor stimulation.

Journal Article Am J Physiol Heart Circ Physiol · February 15, 2015 Chronic stimulation of β-adrenergic receptors (βAR) can promote survival signaling via transactivation of epidermal growth factor receptor (EGFR) but ultimately alters cardiac structure and contractility over time, in part via enhanced cytokine signaling. ... Full text Link to item Cite

Guidelines for translational research in heart failure.

Journal Article J Cardiovasc Transl Res · February 2015 Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropr ... Full text Link to item Cite

Suppression of adrenal βarrestin1-dependent aldosterone production by ARBs: head-to-head comparison.

Journal Article Sci Rep · January 29, 2015 The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion is mediated by either Gq/11 proteins or βarrestin1 (βarr1), both of which can couple to its type 1 receptors (AT₁Rs), present in adrenocortical zona glomerulosa (A ... Full text Link to item Cite

Mitochondrial Fusion Dynamics in the Heart

Conference Biophysical Journal · January 2015 Full text Cite

Chronic β1-adrenergic blockade enhances myocardial β3-adrenergic coupling with nitric oxide-cGMP signaling in a canine model of chronic volume overload: new insight into mechanisms of cardiac benefit with selective β1-blocker therapy.

Journal Article Basic Res Cardiol · January 2015 The β1-adrenergic antagonist metoprolol improves cardiac function in animals and patients with chronic heart failure, isolated mitral regurgitation (MR), and ischemic heart disease, though the molecular mechanisms remain incompletely understood. Metoprolol ... Full text Link to item Cite

The Adrenergic System and Stem Cell-Mediated Myocardial Repair

Chapter · January 1, 2015 The continuous increase of average human life span is yielding a progressively older population pool. With the aging population and increasingly sedentary lifestyle, chronic cardiovascular diseases are approaching epidemic proportions in nearly all develop ... Full text Cite

GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity.

Journal Article Circ Res · December 5, 2014 RATIONALE: G protein-coupled receptor kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be upregulated in failin ... Full text Link to item Cite

Downregulation of G protein-coupled receptor kinase 2 levels enhances cardiac insulin sensitivity and switches on cardioprotective gene expression patterns.

Journal Article Biochim Biophys Acta · December 2014 G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failur ... Full text Link to item Cite

β-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling.

Journal Article Circulation · November 11, 2014 BACKGROUND: Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted ... Full text Link to item Cite

GRK2 in the heart: a GPCR kinase and beyond.

Journal Article Antioxid Redox Signal · November 10, 2014 SIGNIFICANCE: Heart failure (HF) is a common end point for many underlying cardiovascular diseases. Down-regulation and desensitization of β-adrenergic receptors (β-AR) caused by G-protein-coupled receptor (GPCR) kinase 2 (GRK2) are prominent features of H ... Full text Link to item Cite

Activation of liver-X-receptor α but not liver-X-receptor β protects against myocardial ischemia/reperfusion injury.

Journal Article Circ Heart Fail · November 2014 BACKGROUND: Liver-X-receptors, LXRα (NR1H3) and LXRβ (NR1H2), encode 2 different but highly homologous isoforms of transcription factors belonging to the nuclear receptor superfamily. Whether LXRα and LXRβ subtypes have discrete roles in the regulation of ... Full text Link to item Cite

Methods to improve cardiac gene therapy expression.

Journal Article Expert Rev Cardiovasc Ther · November 2014 Gene therapy strategies are becoming a valuable approach for the treatment of heart failure. Some trials are ongoing and others are being organized. Vascular access in clinical experimentation is still the chosen modality of delivery, but many other approa ... Full text Link to item Cite

Identification and characterization of amlexanox as a G protein-coupled receptor kinase 5 inhibitor.

Journal Article Molecules · October 22, 2014 G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective i ... Full text Link to item Cite

Adiponectin regulates SR Ca(2+) cycling following ischemia/reperfusion via sphingosine 1-phosphate-CaMKII signaling in mice.

Journal Article J Mol Cell Cardiol · September 2014 The adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. Recent studies have demonstrated that APN induces a marked Ca(2+) influx in skeletal muscle. However, whether APN modulates [Ca(2+)]i activity, ... Full text Link to item Cite

Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice

Journal Article Pharmacology Research and Perspectives · August 1, 2014 The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined ... Full text Cite

Gi proteins mediate activation of the canonical hedgehog pathway in the myocardium.

Journal Article Am J Physiol Heart Circ Physiol · July 1, 2014 During myocardial ischemia, upregulation of the hedgehog (Hh) pathway promotes neovascularization and increases cardiomyocyte survival. The canonical Hh pathway activates a transcriptional program through the Gli family of transcription factors by derepres ... Full text Link to item Cite

Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy.

Journal Article Expert Rev Cardiovasc Ther · June 2014 It has recently been demonstrated that the apelin receptor (APJ) plays a significant role in mediating the stretch response within the heart in a G-protein-independent and β-arrestin-dependent fashion. This discovery adds to the consolidated literature des ... Full text Link to item Cite

G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism.

Journal Article Circ Res · May 9, 2014 Heart failure (HF) causes a tremendous burden on the worldwide healthcare system, affecting >23 million people. There are many cardiovascular disorders that contribute to the development of HF and multiple risk factors that accelerate its occurrence, but r ... Full text Link to item Cite

Urotensin II promotes vagal-mediated bradycardia by activating cardiac-projecting parasympathetic neurons of nucleus ambiguus.

Journal Article J Neurochem · May 2014 Urotensin II (U-II) is a cyclic undecapeptide that regulates cardiovascular function at central and peripheral sites. The functional role of U-II nucleus ambiguus, a key site controlling cardiac tone, has not been established, despite the identification of ... Full text Link to item Cite

Direct evidence of intracrine angiotensin II signaling in neurons.

Journal Article Am J Physiol Cell Physiol · April 15, 2014 The existence of a local renin-angiotensin system (RAS) in neurons was first postulated 40 years ago. Further studies indicated intraneuronal generation of ANG II. However, the function and signaling mechanisms of intraneuronal ANG II remained elusive. Sin ... Full text Link to item Cite

Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion.

Journal Article Am J Physiol Heart Circ Physiol · April 1, 2014 Phospholemman (PLM), when phosphorylated at Ser(68), inhibits cardiac Na+ / Ca2+ exchanger 1 (NCX1) and relieves its inhibition on Na+ -K+ -ATPase. We have engineered mice in which expression of the phosphomimetic PLM S68E mutant was induced when dietary d ... Full text Link to item Cite

TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria.

Journal Article J Biol Chem · March 14, 2014 Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate-ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 ± 0.02. To explore the cellular mechanisms by which TRPM2 chann ... Full text Link to item Cite

SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death.

Journal Article Mol Biol Cell · March 2014 Emerging findings suggest that two lineages of mitochondrial Ca(2+) uptake participate during active and resting states: 1) the major eukaryotic membrane potential-dependent mitochondrial Ca(2+) uniporter and 2) the evolutionarily conserved exchangers and ... Full text Link to item Cite

β-arrestin1-biased β1-adrenergic receptor signaling regulates microRNA processing.

Journal Article Circ Res · February 28, 2014 RATIONALE: MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin int ... Full text Open Access Link to item Cite

Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.

Journal Article Circ Res · February 28, 2014 RATIONALE: Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered. OBJECTIVE: The current study attempted to identify the adiponectin receptor subtype responsible for adip ... Full text Link to item Cite

Changes of plasma norepinephrine and serum N-terminal pro-brain natriuretic peptide after exercise training predict survival in patients with heart failure.

Journal Article Int J Cardiol · February 15, 2014 BACKGROUND: Short-term changes of neurohormones can give important prognostic information in heart failure (HF) patients. In this study, we evaluate whether changes in plasma Norepinephrine (NE) and serum N-terminal pro-brain natriuretic peptide (NT-proBNP ... Full text Link to item Cite

Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.

Journal Article Hypertension · February 2014 β-Arrestin (βarr)-1 and β-arrestin-2 (βarrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac β-adrenergic receptor (βAR) function via βAR desensitization and downregulation. In addition, they mediate G-protein-ind ... Full text Open Access Link to item Cite

Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.

Journal Article Gene Ther · February 2014 Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocard ... Full text Link to item Cite

Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation.

Journal Article J Heart Lung Transplant · February 2014 BACKGROUND: Mechanical unloading of failing hearts can trigger functional recovery but results in progressive atrophy and possibly detrimental adaptation. In an unbiased approach, we examined the dynamic effects of unloading duration on molecular markers i ... Full text Link to item Cite

p38α regulates SERCA2a function.

Journal Article J Mol Cell Cardiol · February 2014 cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile ... Full text Link to item Cite

Cardiovascular gene therapy for myocardial infarction.

Journal Article Expert Opin Biol Ther · February 2014 INTRODUCTION: Cardiovascular gene therapy is the third most popular application for gene therapy, representing 8.4% of all gene therapy trials as reported in 2012 estimates. Gene therapy in cardiovascular disease is aiming to treat heart failure from ische ... Full text Link to item Cite

Dynamic mass redistribution analysis of endogenous β-adrenergic receptor signaling in neonatal rat cardiac fibroblasts

Journal Article Pharmacology Research and Perspectives · February 1, 2014 Label-free systems for the agnostic assessment of cellular responses to receptor stimulation have been shown to provide a sensitive method to dissect receptor signaling. β-adenergic receptors (βAR) are important regulators of normal and pathologic cardiac ... Full text Cite

Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure.

Journal Article Eur J Prev Cardiol · January 2014 BACKGROUND: Increased cardiac G protein-coupled receptor kinase-2 (GRK2) expression has a pivotal role at inducing heart failure (HF)-related β-adrenergic receptor (βAR) dysfunction. Importantly, abnormalities of βAR signalling in the failing heart, includ ... Full text Link to item Cite

Elucidating the role of GRK5 in Physiological Hypertrophy

Conference CIRCULATION RESEARCH · 2014 Cite

Cardiac progenitor cells engineered with βARKct have enhanced β-adrenergic tolerance.

Journal Article Mol Ther · January 2014 Stem cell survival and retention in myocardium after injury following adoptive transfer is low. Elevated catecholamine levels coinciding with myocardial injury adversely affect cardiac progenitor cell (CPC) survival. The G protein-coupled receptor kinase 2 ... Full text Link to item Cite

Adiponectin inhibits oxidative/nitrative stress during myocardial ischemia and reperfusion via PKA signaling

Journal Article American Journal of Physiology Endocrinology and Metabolism · December 15, 2013 The cardioprotective effects of adiponectin (APN) against myocardial ischemia/reperfusion (MI/R) injury are well known. However, comprehension of the mechanisms mediating intracellular APN signaling remains incomplete. We recently demonstrate the antioxida ... Full text Cite

Regulation of nuclear factor κB (NF-κB) in the nucleus of cardiomyocytes by G protein-coupled receptor kinase 5 (GRK5).

Journal Article J Biol Chem · December 13, 2013 G protein-coupled receptor kinase 5 GRK5 plays a key role in regulating cardiac signaling and its expression is increased in heart failure. GRK5 activity in the nucleus of myocytes has been shown to be detrimental in the setting of pressure-overload hypert ... Full text Link to item Cite

Ethanol stimulates angiogenesis via vascular endothelial growth factor and protects from ischemia and reperfusion injury

Chapter · December 1, 2013 The cardioprotective effects of moderate ethanol consumption have been known for years and have generally been ascribed to long-term effects of alcohol on blood lipids. However, other mechanisms, particularly ethanol-induced angiogenesis, may also be invol ... Cite

Vascular endothelial growth factor blockade prevents the beneficial effects of β-blocker therapy on cardiac function, angiogenesis, and remodeling in heart failure.

Journal Article Circ Heart Fail · November 2013 BACKGROUND: Impaired angiogenesis in the post-myocardial infarction heart contributes to the progression to heart failure. The inhibition of vascular endothelial growth factor (VEGF) signaling has been shown to be crucial for the transition from compensato ... Full text Link to item Cite

Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury.

Journal Article Science signaling · October 29, 2013 Heart failure caused by ischemic heart disease is a leading cause of death in the developed world. Treatment is currently centered on regimens involving G protein-coupled receptors (GPCRs) or nitric oxide (NO). These regimens are thought to target distinct ... Cite

Science signaling podcast: 29 october 2013

Journal Article Science Signaling · October 29, 2013 This Podcast features an interview with Walter Koch, senior author of a Research Article that appears in the 29 October 2013 issue of Science Signaling, about a posttranslational modification that can help prevent the death of cardiac myocytes in the conte ... Full text Cite

Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury.

Journal Article Sci Signal · October 29, 2013 Heart failure caused by ischemic heart disease is a leading cause of death in the developed world. Treatment is currently centered on regimens involving G protein-coupled receptors (GPCRs) or nitric oxide (NO). These regimens are thought to target distinct ... Full text Link to item Cite

Targeting cardiac β-adrenergic signaling via GRK2 inhibition for heart failure therapy

Journal Article Frontiers in Physiology · October 16, 2013 Cardiac cells, like those of the other tissues, undergo regulation through membrane-bound proteins known as G protein-coupled receptors (GPCRs). β-adrenergic receptors (βARs) are key GPCRs expressed on cardiomyocytes and their role is crucial in cardiac ph ... Full text Cite

β1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: protective role of S1PR1 cardiac gene therapy.

Journal Article Circulation · October 8, 2013 BACKGROUND: The sphingosine-1-phosphate receptor 1 (S1PR1) and β1-adrenergic receptor (β1AR) are G-protein-coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Imp ... Full text Link to item Cite

Differential regulation of TNF receptor 1 and receptor 2 in adiponectin expression following myocardial ischemia.

Journal Article Int J Cardiol · October 3, 2013 BACKGROUND: In vitro experiments demonstrate that adiponectin, a cardioprotective cytokine, is inhibited by tumor necrosis factor-alpha (TNFα). However, the role of TNFα in post-myocardial infarction (post-MI) adiponectin reduction remains unclear. More im ... Full text Link to item Cite

TNF-α induces phenotypic modulation in cerebral vascular smooth muscle cells: implications for cerebral aneurysm pathology.

Journal Article J Cereb Blood Flow Metab · October 2013 Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF-α) has been associated with aneurysms, but potential mechanisms are unclea ... Full text Open Access Link to item Cite

Prothymosin alpha protects cardiomyocytes against ischemia-induced apoptosis via preservation of Akt activation.

Journal Article Apoptosis · October 2013 The human prothymosin alpha (PTα) gene encodes a 12.5 kDa highly acidic nuclear protein that is widely expressed in mammalian tissues including the heart and importantly, is detectable also in blood serum. During apoptosis or necrosis, PTα changes its nucl ... Full text Link to item Cite

Sevoflurane preconditioning attenuates myocardial ischemia/reperfusion injury via caveolin-3-dependent cyclooxygenase-2 inhibition.

Conference Circulation · September 10, 2013 BACKGROUND: The inhaled anesthetic sevoflurane has been demonstrated to protect against myocardial ischemia/reperfusion (MI/R) injury via mechanisms involving AMP-activated protein kinase (AMPK) and caveolin-3 (Cav-3). However, the relative contributions o ... Full text Link to item Cite

C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase A activation.

Conference Circulation · September 10, 2013 BACKGROUND: C1q/tumor necrosis factor-related protein-9 (CTRP9) is a newly identified adiponectin paralog with established metabolic regulatory properties. However, the role of CTRP9 in postmyocardial infarction remodeling remains completely unknown. This ... Full text Link to item Cite

Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation.

Journal Article J Physiol · September 1, 2013 In addition to acting on mineralocorticoid receptors, aldosterone has been recently shown to activate the G protein-coupled oestrogen receptor (GPER) in vascular cells. In light of the newly identified role for GPER in vagal cardiac control, we examined wh ... Full text Link to item Cite

Nesfatin-1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats.

Journal Article J Neurochem · September 2013 Nesfatin-1, a peptide whose receptor is yet to be identified, has been involved in the modulation of feeding, stress, and metabolic responses. More recently, increasing evidence supports a modulatory role for nesfatin-1 in autonomic and cardiovascular acti ... Full text Link to item Cite

GRK2 negatively regulates IGF-1R signaling pathway and cyclins' expression in HepG2 cells.

Journal Article J Cell Physiol · September 2013 G protein coupled receptor kinase 2 (GRK2) plays a central role in the regulation of a variety of important signaling pathways. Alternation of GRK2 protein level and activity casts profound effects on cell physiological functions and causes diseases such a ... Full text Link to item Cite

Heart failure gene therapy: the path to clinical practice.

Journal Article Circ Res · August 30, 2013 Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therape ... Full text Link to item Cite

Adrenergic nervous system in heart failure: pathophysiology and therapy.

Journal Article Circ Res · August 30, 2013 Heart failure (HF), the leading cause of death in the western world, develops when a cardiac injury or insult impairs the ability of the heart to pump blood and maintain tissue perfusion. It is characterized by a complex interplay of several neurohormonal ... Full text Link to item Cite

GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility.

Journal Article Cell Commun Signal · August 28, 2013 BACKGROUND: β1- and β2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes β ... Full text Open Access Link to item Cite

Differential activation of cultured neonatal cardiomyocytes by plasmalemmal versus intracellular G protein-coupled receptor 55.

Journal Article J Biol Chem · August 2, 2013 The L-α-lysophosphatidylinositol (LPI)-sensitive receptor GPR55 is coupled to Ca(2+) signaling. Low levels of GPR55 expression in the heart have been reported. Similar to other G protein-coupled receptors involved in cardiac function, GPR55 may be expresse ... Full text Link to item Cite

The role of oxidative stress in cerebral aneurysm formation and rupture.

Journal Article Curr Neurovasc Res · August 2013 Oxidative stress is known to contribute to the progression of cerebrovascular disease. Additionally, oxidative stress may be increased by, but also augment inflammation, a key contributor to cerebral aneurysm development and rupture. Oxidative stress can i ... Full text Link to item Cite

Activation of hypoxia response in endothelial cells contributes to ischemic cardioprotection.

Journal Article Mol Cell Biol · August 2013 Small-molecule inhibition of hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs) is being explored for the treatment of anemia. Previous studies have suggested that HIF-P4H-2 inhibition may also protect the heart from an ischemic insult. Hif-p4h-2(gt ... Full text Link to item Cite

Gene therapy for heart disease: molecular targets, vectors and modes of delivery to myocardium.

Journal Article Expert Rev Cardiovasc Ther · August 2013 Despite the numerous hurdles that gene therapy has encountered along the way, clinical trials over the last few years are showing promising results in many fields of medicine, including cardiology, where many targets are moving toward clinical development. ... Full text Link to item Cite

Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury.

Journal Article Eur Heart J · June 2013 AIMS: Emerging evidence indicates that nuclear receptors play a critical regulatory role in cardiovascular physiology/pathology. Recently, farnesoid-X-receptor (FXR), a member of the metabolic nuclear receptor superfamily, has been demonstrated to be expre ... Full text Link to item Cite

AAV6.βARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model.

Journal Article Eur Heart J · May 2013 AIMS: G protein-coupled receptor kinase 2 (GRK2), which is markedly upregulated in failing human myocardium, has been implicated as a contributing factor or consequence of heart failure (HF). Importantly, cardiac-specific GRK2 knockout mice have recently p ... Full text Link to item Cite

Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting.

Journal Article Circ Res · April 12, 2013 RATIONALE: G protein-coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ... Full text Link to item Cite

The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury.

Journal Article Am J Physiol Heart Circ Physiol · April 1, 2013 The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 ... Full text Link to item Cite

MCARD-mediated gene transfer of GRK2 inhibitor in ovine model of acute myocardial infarction.

Journal Article J Cardiovasc Transl Res · April 2013 β-Adrenergic receptor (βAR) dysfunction in acute myocardial infarction (MI) is associated with elevated levels of the G-protein-coupled receptor kinase-2 (GRK2), which plays a key role in heart failure progression. Inhibition of GRK2 via expression of a pe ... Full text Link to item Cite

Lymphotoxin-α is a novel adiponectin expression suppressor following myocardial ischemia/reperfusion.

Journal Article Am J Physiol Endocrinol Metab · March 15, 2013 Recent clinical observations demonstrate adiponectin (APN), an adipocytokine with potent cardioprotective actions, is significantly reduced following myocardial ischemia/reperfusion (MI/R). However, mechanisms responsible for MI/R-induced hypoadiponectinem ... Full text Link to item Cite

β-Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation.

Journal Article Circ Res · February 1, 2013 RATIONALE: Short-term β-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offs ... Full text Link to item Cite

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation.

Journal Article J Clin Invest · February 2013 During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca2+ overload. ... Full text Link to item Cite

S100A1 deficiency impairs postischemic angiogenesis via compromised proangiogenic endothelial cell function and nitric oxide synthase regulation.

Journal Article Circ Res · January 4, 2013 RATIONALE: Mice lacking the EF-hand Ca2+ sensor S100A1 display endothelial dysfunction because of distorted Ca2+ -activated nitric oxide (NO) generation. OBJECTIVE: To determine the pathophysiological role of S100A1 in endothelial cell (EC) function in exp ... Full text Link to item Cite

Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease.

Journal Article PLoS One · 2013 BACKGROUND: The role of smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation and pathogenesis of stroke has not been determined. Cigarette smoke is a major risk factor for atherosclerosis, but potential mechanisms are unclear, and its ... Full text Open Access Link to item Cite

Coordinated regulation of cardiac Na(+)/Ca (2+) exchanger and Na (+)-K (+)-ATPase by phospholemman (FXYD1).

Conference Adv Exp Med Biol · 2013 Phospholemman (PLM) is the founding member of the FXYD family of regulators of ion transport. PLM is a 72-amino acid protein consisting of the signature PFXYD motif in the extracellular N terminus, a single transmembrane (TM) domain, and a C-terminal cytop ... Full text Link to item Cite

Inhibition of p38a Regulates SERCA2a Function

Conference CIRCULATION RESEARCH · 2013 Cite

GRK5 Increases Cardiac NFAT Transcriptional Activity

Conference CIRCULATION RESEARCH · 2013 Cite

A novel and efficient model of coronary artery ligation in the mouse.

Chapter · 2013 Coronary artery ligation to induce myocardial infarction (MI) and ischemia/reperfusion (I/R) injury in mice is typically performed by an invasive and time-consuming approach that requires ventilation and a full thoracotomy (classical method), often resulti ... Full text Link to item Cite

Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway.

Journal Article PLoS One · 2013 Studies from our lab have shown that decreasing myocardial G protein-coupled receptor kinase 2 (GRK2) activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro-death kinase in myocyte ... Full text Link to item Cite

Tumor necrosis factor-α and lymphotoxin-α mediate myocardial ischemic injury via TNF receptor 1, but are cardioprotective when activating TNF receptor 2.

Journal Article PLoS One · 2013 OBJECTIVE: This study determines the roles of tumor necrosis factor-α (TNFα) and lymphotoxin-α (LTα) in post-myocardial infarction (post-MI) cardiac injury, and identifies the TNF receptor type responsible for TNFα- and LTα-mediated cardiac injury. METHODS ... Full text Link to item Cite

Nuclear translocation of cardiac G protein-Coupled Receptor kinase 5 downstream of select Gq-activating hypertrophic ligands is a calmodulin-dependent process.

Journal Article PLoS One · 2013 G protein-Coupled Receptors (GPCRs) kinases (GRKs) play a crucial role in regulating cardiac hypertrophy. Recent data from our lab has shown that, following ventricular pressure overload, GRK5, a primary cardiac GRK, facilitates maladaptive myocyte growth ... Full text Link to item Cite

Induced overexpression of Na(+)/Ca(2+) exchanger does not aggravate myocardial dysfunction induced by transverse aortic constriction.

Journal Article J Card Fail · January 2013 BACKGROUND: Alterations in expression and activity of cardiac Na(+)/Ca(2+) exchanger (NCX1) have been implicated in the pathogenesis of heart failure. METHODS AND RESULTS: Using transgenic mice in which expression of rat NCX1 was induced at 5 weeks of age, ... Full text Link to item Cite

Inhibition of CTRP9, a novel and cardiac-abundantly expressed cell survival molecule, by TNFα-initiated oxidative signaling contributes to exacerbated cardiac injury in diabetic mice.

Journal Article Basic Res Cardiol · January 2013 Recently identified as adiponectin (APN) paralogs, C1q/TNF-related proteins (CTRPs) share similar metabolic regulatory functions as APN. The current study determined cardiac expression of CTRPs, their potential cardioprotective function, and investigated w ... Full text Link to item Cite

Intracellular endothelin type B receptor-driven Ca2+ signal elicits nitric oxide production in endothelial cells.

Journal Article J Biol Chem · November 30, 2012 Endothelin-1 exerts its actions via activation of ET(A) and ET(B) G(q/11) protein-coupled receptors, located in the plasmalemma, cytoplasm, and nucleus. Although the autocrine/paracrine nature of endothelin-1 signaling has been extensively studied, its int ... Full text Link to item Cite

Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility.

Journal Article ACS Chem Biol · November 16, 2012 G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. Herein we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro ... Full text Link to item Cite

The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury.

Journal Article Am J Physiol Endocrinol Metab · October 1, 2012 The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing roles in diabetic myocardial ischemia-reperfusion (MI/R) injury. We recently demonstrated nitrative modification of Trx leads to its inactivation and loss of cardio ... Full text Link to item Cite

Determining the absolute requirement of G protein-coupled receptor kinase 5 for pathological cardiac hypertrophy: short communication.

Journal Article Circ Res · September 28, 2012 RATIONALE: Heart failure (HF) is often the end phase of maladaptive cardiac hypertrophy. A contributing factor is activation of a hypertrophic gene expression program controlled by decreased class II histone deacetylase (HDAC) transcriptional repression vi ... Full text Open Access Link to item Cite

Biology of intracranial aneurysms: role of inflammation.

Journal Article J Cereb Blood Flow Metab · September 2012 Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body ... Full text Open Access Link to item Cite

Ethanol protects from injury due to ischemia and reperfusion by increasing vascularity via vascular endothelial growth factor.

Journal Article Alcohol · August 2012 UNLABELLED: The cardioprotective effects of moderate ethanol consumption have been known for years and have generally been ascribed to long-term effects of alcohol on blood lipids. However, other mechanisms, particularly ethanol-induced increase in blood v ... Full text Link to item Cite

Beta1-adrenergic receptors promote focal adhesion signaling downregulation and myocyte apoptosis in acute volume overload.

Journal Article J Mol Cell Cardiol · August 2012 Numerous studies demonstrated increased expression of extracellular matrix (ECM) proteins and activation of focal adhesion (FA) signaling pathways in models of pressure overload-induced cardiac hypertrophy. However, little is known about FA signaling in re ... Full text Link to item Cite

Blockade of β-adrenoceptors restores the GRK2-mediated adrenal α(2) -adrenoceptor-catecholamine production axis in heart failure.

Journal Article Br J Pharmacol · August 2012 BACKGROUND AND PURPOSE: Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of β-adrenoceptor antagonist (β-blockers) therapy in HF is primarily attributed to prote ... Full text Link to item Cite

Myocardial β(2) -adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure.

Journal Article Br J Pharmacol · August 2012 BACKGROUND AND PURPOSE: We investigated whether β(2) -adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. EXPERIMENTAL APPROACH: We explored the angiogenic effects of ... Full text Link to item Cite

CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy.

Journal Article Cell Cycle · July 15, 2012 Triple-negative breast cancer (TNBC) is an aggressive disease that lacks established markers to direct therapeutic intervention. Thus, these tumors are routinely treated with cytotoxic chemotherapies (e.g., anthracyclines), which can cause severe side effe ... Full text Link to item Cite

C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart.

Journal Article Circulation · June 26, 2012 BACKGROUND: Obesity and diabetes mellitus adversely affect postischemic heart remodeling via incompletely understood mechanisms. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation, s ... Full text Link to item Cite

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade.

Journal Article Gene Ther · June 2012 Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symp ... Full text Link to item Cite

Growth inhibition of human hepatocellular carcinoma cells by overexpression of G-protein-coupled receptor kinase 2.

Journal Article J Cell Physiol · June 2012 Hepatocellular carcinoma (HCC) is one of the deadliest forms of human liver cancer and does not respond well to conventional therapies. Novel effective treatments are urgently in need. G-protein-coupled kinase 2 (GRK2) is unique serine/threonine kinase tha ... Full text Link to item Cite

Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction.

Journal Article Circulation · May 1, 2012 BACKGROUND: G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of β-adrenergic signaling in the heart. G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been ac ... Full text Link to item Cite

Involvement of nuclear factor κB (NF-κB) signaling pathway in regulation of cardiac G protein-coupled receptor kinase 5 (GRK5) expression.

Journal Article J Biol Chem · April 13, 2012 G protein-coupled receptor kinase 5 (GRK5) plays a key role in cardiac signaling regulation, and its expression is increased in heart failure. Recently, increased expression of GRK5 in the myocardium of mice has been shown to be detrimental in the setting ... Full text Link to item Cite

363 Apoptosis Occurs in Late Stages of Unloading Related Ventricular Remodeling

Conference The Journal of Heart and Lung Transplantation · April 2012 Full text Cite

Essential role of caveolin-3 in adiponectin signalsome formation and adiponectin cardioprotection.

Journal Article Arterioscler Thromb Vasc Biol · April 2012 OBJECTIVE: Adiponectin (APN) system malfunction is causatively related to increased cardiovascular morbidity/mortality in diabetic patients. The aim of the current study was to investigate molecular mechanisms responsible for APN transmembrane signaling an ... Full text Link to item Cite

Hyperphosphorylation of the cardiac ryanodine receptor at serine 2808 is not involved in cardiac dysfunction after myocardial infarction.

Journal Article Circ Res · March 16, 2012 RATIONALE: Abnormal behavior of the cardiac ryanodine receptor (RyR2) has been linked to cardiac arrhythmias and heart failure (HF) after myocardial infarction (MI). It has been proposed that protein kinase A (PKA) hyperphosphorylation of the RyR2 at a sin ... Full text Link to item Cite

Constitutive overexpression of phosphomimetic phospholemman S68E mutant results in arrhythmias, early mortality, and heart failure: potential involvement of Na+/Ca2+ exchanger.

Journal Article Am J Physiol Heart Circ Physiol · February 1, 2012 Expression and activity of cardiac Na(+)/Ca(2+) exchanger (NCX1) are altered in many disease states. We engineered mice in which the phosphomimetic phospholemman S68E mutant (inhibits NCX1 but not Na(+)-K(+)-ATPase) was constitutively overexpressed in a ca ... Full text Link to item Cite

Gi-biased β2AR signaling links GRK2 upregulation to heart failure.

Journal Article Circ Res · January 20, 2012 RATIONALE: Phosphorylation of β(2)-adrenergic receptor (β(2)AR) by a family of serine/threonine kinases known as G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein-cou ... Full text Open Access Link to item Cite

Cigarette smoke and inflammation: role in cerebral aneurysm formation and rupture.

Journal Article Mediators Inflamm · 2012 Smoking is an established risk factor for subarachnoid hemorrhage yet the underlying mechanisms are largely unknown. Recent data has implicated a role of inflammation in the development of cerebral aneurysms. Inflammation accompanying cigarette smoke expos ... Full text Link to item Cite

G protein-coupled receptor kinases: Molecular mechanism and inhibition

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · 2012 Cite

GRK2 inhibition in heart failure: something old, something new.

Journal Article Curr Pharm Des · 2012 Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains the number one killer disease in the western world. HF is a chronic and progressive clinical syndrome mainly characterized by reduction in left ventricular e ... Full text Link to item Cite

G protein-coupled receptor kinase 2 as a therapeutic target for heart failure

Journal Article Drug Discovery Today Therapeutic Strategies · January 1, 2012 An ever-increasing number of people world-wide are developing and suffering from heart failure, and existing therapies, although improved are not ideal. Therefore, innovative treatment strategies are urgently needed. As our understanding of the underlying ... Full text Cite

Cardioprotection of controlled and cardiac-specific over-expression of A(2A)-adenosine receptor in the pressure overload.

Journal Article PLoS One · 2012 Adenosine binds to three G protein-coupled receptors (R) located on the cardiomyocyte (A(1)-R, A(2A)-R and A(3)-R) and provides cardiac protection during both ischemic and load-induced stress. While the role of adenosine receptor-subtypes has been well def ... Full text Link to item Cite

Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction.

Journal Article J Mol Cell Cardiol · January 2012 Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated dur ... Full text Link to item Cite

A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity.

Journal Article Circ Res · December 9, 2011 RATIONALE: Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. Sorafenib is a KI of concern because it inhibits growth factor receptors ... Full text Link to item Cite

Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density.

Journal Article Am J Physiol Heart Circ Physiol · November 2011 Akt2 protein kinase has been shown to promote cell migration and actin polymerization in several cell types, including macrophages. Because migrating macrophages constitute an important inflammatory response after myocardial ischemia, we determined cardiac ... Full text Link to item Cite

Gene therapy targets in heart failure: the path to translation.

Journal Article Clin Pharmacol Ther · October 2011 Heart failure (HF) is the common end point of cardiac diseases. Despite the optimization of therapeutic strategies and the consequent overall reduction in HF-related mortality, the key underlying intracellular signal transduction abnormalities have not bee ... Full text Link to item Cite

Reduced cardioprotective action of adiponectin in high-fat diet-induced type II diabetic mice and its underlying mechanisms.

Journal Article Antioxid Redox Signal · October 1, 2011 Diabetes exacerbates ischemic heart disease morbidity and mortality via incompletely understood mechanisms. Although adiponectin (APN) reduces myocardial ischemia/reperfusion (MI/R) injury in nondiabetic animals, whether APN's cardioprotective actions are ... Full text Link to item Cite

Nuclear effects of G-protein receptor kinase 5 on histone deacetylase 5-regulated gene transcription in heart failure.

Journal Article Circ Heart Fail · September 2011 BACKGROUND: G-protein receptor kinases (GRKs) modulate cardiac β-adrenergic signaling. GRK5 is upregulated in heart failure, and a gain-of-function polymorphism substituting leucine for wild-type glutamine at amino acid 41 (GRK5-Leu41) is associated with i ... Full text Link to item Cite

S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes.

Journal Article J Am Coll Cardiol · August 23, 2011 OBJECTIVES: This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs). BACKGROUND: Depletion of the Ca²⁺-sensor protein S100A1 drives deterioration of cardia ... Full text Link to item Cite

Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling.

Journal Article Circulation · August 2, 2011 BACKGROUND: [Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated sign ... Full text Open Access Link to item Cite

A pharmacokinetic analysis of molecular cardiac surgery with recirculation mediated delivery of βARKct gene therapy: developing a quantitative definition of the therapeutic window.

Journal Article J Card Fail · August 2011 BACKGROUND: Two major problems for translating gene therapy for heart failure therapy are: safe and efficient delivery and the inability to establish a relationship between vector exposure and in vivo effects. We present a pharmacokinetics (PK) analysis of ... Full text Link to item Cite

Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model.

Journal Article Sci Transl Med · July 20, 2011 As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (AAV)-S100A1 gene therapy in a preclinical large animal model of heart failure. S100A1, a positive inotropic regulator of ... Full text Link to item Cite

A role for GRK2 in myocardial ischemic injury: indicators of a potential future therapy and diagnostic.

Journal Article Future Cardiol · July 2011 Morbidity and mortality of myocardial infarction remains significant with resulting left ventricular function presenting as a major determinant of clinical outcome. Protecting the myocardium against ischemia reperfusion injury has become a major therapeuti ... Full text Link to item Cite

Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo.

Journal Article Gene Ther · June 2011 We use a novel technique that allows for closed recirculation of vector genomes in the cardiac circulation using cardiopulmonary bypass, referred to here as molecular cardiac surgery with recirculating delivery (MCARD). We demonstrate that this platform te ... Full text Link to item Cite

G protein-coupled receptor kinases in normal and failing myocardium.

Journal Article Front Biosci (Landmark Ed) · June 1, 2011 Heart failure (HF) is the end stage of many underlying cardiovascular diseases and is among the leading causes of morbidity and mortality in industrialized countries. One of the striking characteristics of HF is the desensitization of G protein-coupled rec ... Full text Link to item Cite

G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia.

Journal Article Circulation · May 10, 2011 BACKGROUND: Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure. The chronic adrenergic stimulation that accompanies heart failure is a signaling abnormality that leads t ... Full text Link to item Cite

GRK2 as a novel gene therapy target in heart failure.

Journal Article J Mol Cell Cardiol · May 2011 Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. HF is a chronic and progressive clinical syndrome characterized by a reduction in left ventricular (LV) ... Full text Link to item Cite

Abstract 591: Expanding the therapeutic window through pharmacological activation of the RB pathway in breast cancer treatment

Conference Cancer Research · April 15, 2011 AbstractTriple negative breast cancer (TNBC) is a highly aggressive disease that is most often treated with cytotoxic chemotherapies, such as anthracyclines and platinum compounds. While effective for certai ... Full text Cite

Caveolin-1 deficiency exacerbates cardiac dysfunction and reduces survival in mice with myocardial infarction.

Journal Article Am J Physiol Heart Circ Physiol · April 2011 Caveolin (Cav)-1 has been involved in the pathogenesis of ischemic injuries. For instance, modulations of Cav-1 expression have been reported in animal models of myocardial infarction and cerebral ischemia-reperfusion. Furthermore, ablation of the Cav-1 ge ... Full text Link to item Cite

S100A1 GENETICALLY TARGETED THERAPY REVERSES DYSFUNCTION OF HUMAN FAILING MYOCARDIUM

Conference Journal of the American College of Cardiology · April 2011 Full text Cite

Regulation of in vivo cardiac contractility by phospholemman: role of Na+/Ca2+ exchange.

Journal Article Am J Physiol Heart Circ Physiol · March 2011 Phospholemman (PLM), when phosphorylated at serine 68, relieves its inhibition on Na(+)-K(+)-ATPase but inhibits Na(+)/Ca(2+) exchanger 1 (NCX1) in cardiac myocytes. Under stress when catecholamine levels are high, enhanced Na(+)-K(+)-ATPase activity by ph ... Full text Link to item Cite

Cardiomyocyte lipids impair β-adrenergic receptor function via PKC activation.

Journal Article Am J Physiol Endocrinol Metab · March 2011 Normal hearts have increased contractility in response to catecholamines. Because several lipids activate PKCs, we hypothesized that excess cellular lipids would inhibit cardiomyocyte responsiveness to adrenergic stimuli. Cardiomyocytes treated with satura ... Full text Link to item Cite

Calcium influx through Cav1.2 is a proximal signal for pathological cardiomyocyte hypertrophy.

Journal Article J Mol Cell Cardiol · March 2011 Pathological cardiac hypertrophy (PCH) is associated with the development of arrhythmia and congestive heart failure. While calcium (Ca(2+)) is implicated in hypertrophic signaling pathways, the specific role of Ca(2+) influx through the L-type Ca(2+) chan ... Full text Link to item Cite

Left ventricular dysfunction in murine models of heart failure and in failing human heart is associated with a selective decrease in the expression of caveolin-3.

Journal Article J Card Fail · March 2011 BACKGROUND: Caveolins are scaffolding proteins that are integral components of caveolae, flask-shaped invaginations in the membranes of all mammalian cells. Caveolin-1 and -2 are expressed ubiquitously, whereas caveolin-3 is found only in muscle. The role ... Full text Link to item Cite

Impaired neoangiogenesis in β₂-adrenoceptor gene-deficient mice: restoration by intravascular human β₂-adrenoceptor gene transfer and role of NFκB and CREB transcription factors.

Journal Article Br J Pharmacol · February 2011 BACKGROUND AND PURPOSE: There is much evidence supporting the role of β₂-adrenoceptors (β₂AR) in angiogenesis but the mechanisms underlying their effects have not been elucidated. Hence, we studied post-ischaemic angiogenesis in the hindlimb (HL) of β₂AR k ... Full text Link to item Cite

Adrenal beta-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels.

Journal Article J Am Coll Cardiol · January 18, 2011 OBJECTIVES: We investigated whether adrenal beta-arrestin 1 (βarr1)-mediated aldosterone production plays any role in post-myocardial infarction (MI) heart failure (HF) progression. BACKGROUND: Heart failure represents 1 of the most significant health prob ... Full text Link to item Cite

The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition.

Journal Article Circ Res · January 7, 2011 RATIONALE: The G(βγ)-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP sig ... Full text Link to item Cite

Downregulation of adiponectin induced by tumor necrosis factor α is involved in the aggravation of posttraumatic myocardial ischemia/reperfusion injury

Journal Article Critical Care Medicine · January 1, 2011 Objective: Recent clinical observations have indicated that nonlethal mechanical trauma significantly increases myocardial infarction risk even in the presence of completely normal coronary arteries. We investigated the molecular mechanisms responsible for ... Full text Cite

A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse.

Journal Article Circ Res · December 10, 2010 RATIONALE: coronary artery ligation to induce myocardial infarction (MI) in mice is typically performed by an invasive and time-consuming approach that requires ventilation and chest opening (classic method), often resulting in extensive tissue damage and ... Full text Link to item Cite

Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms.

Journal Article Circ Res · October 29, 2010 RATIONALE: Activation of prosurvival kinases and subsequent nitric oxide (NO) production by certain G protein-coupled receptors (GPCRs) protects myocardium in ischemia/reperfusion injury (I/R) models. GPCR signaling pathways are regulated by GPCR kinases ( ... Full text Link to item Cite

betaARKct: a therapeutic approach for improved adrenergic signaling and function in heart disease.

Journal Article J Cardiovasc Transl Res · October 2010 One of the most powerful regulators of cardiovascular function is catecholamine-stimulated adrenergic receptor (AR) signaling. The failing heart is characterized by desensitization and impaired beta-AR responsiveness as a result of upregulated G protein-co ... Full text Link to item Cite

Increasing cardiac contractility after myocardial infarction exacerbates cardiac injury and pump dysfunction.

Journal Article Circ Res · September 17, 2010 RATIONALE: Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined and are the focus of this study. ... Full text Link to item Cite

Advancing the research mission in an academic department: the creation of a center for translational medicine.

Journal Article Clin Transl Sci · August 2010 Multidisciplinary research centers have multiplied in academic medical centers over the past decade and several recent reports have described their structure, strengths and limitations, and the difficulties that they may face. However, little attention has ... Full text Link to item Cite

GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice.

Journal Article J Clin Invest · July 2010 The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isofor ... Full text Link to item Cite

Comparative cardiac gene delivery of adeno-associated virus serotypes 1-9 reveals that AAV6 mediates the most efficient transduction in mouse heart.

Journal Article Clin Transl Sci · June 2010 Cardiac gene transfer is an attractive tool for developing novel heart disease treatments. Adeno-associated viral (AAV) vectors are widely used to mediate transgene expression in animal models and are being evaluated for human gene therapy. However, it is ... Full text Link to item Cite

Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes.

Journal Article J Mol Cell Cardiol · June 2010 Cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signalling pathways dependent on extracellular calcium (Ca(2+)) influx that control normal and pathological cardiac growth may enable identification of novel th ... Full text Link to item Cite

Adrenal GRK2 lowering is an underlying mechanism for the beneficial sympathetic effects of exercise training in heart failure.

Journal Article Am J Physiol Heart Circ Physiol · June 2010 Exercise training has been reported to exert beneficial effects on cardiac function and to reduce morbidity and mortality of chronic heart failure (HF). Augmented sympathetic nervous system (SNS) activity, leading to elevated circulating catecholamine (CA) ... Full text Link to item Cite

Targeting G protein-coupled receptor kinases (GRKs) in heart failure

Journal Article Drug Discovery Today Disease Mechanisms · June 1, 2010 In the human body, over 1000 different G protein-coupled receptors (GPCRs) mediate a broad spectrum of extracellular signals at the plasma membrane, transmitting vital physiological features such as pain, sight, smell, inflammation, heart rate and contract ... Full text Cite

Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction.

Journal Article J Biol Chem · May 21, 2010 Chronic heart failure (HF) is characterized by sympathetic overactivity and enhanced circulating catecholamines (CAs), which significantly increase HF morbidity and mortality. We recently reported that adrenal G protein-coupled receptor kinase 2 (GRK2) is ... Full text Link to item Cite

Phospholemman and beta-adrenergic stimulation in the heart.

Journal Article Am J Physiol Heart Circ Physiol · March 2010 Phosphorylation at serine 68 of phospholemman (PLM) in response to beta-adrenergic stimulation results in simultaneous inhibition of cardiac Na(+)/Ca(2+) exchanger NCX1 and relief of inhibition of Na(+)-K(+)-ATPase. The role of PLM in mediating beta-adrene ... Full text Link to item Cite

Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia-reperfusion injury.

Journal Article Am J Physiol Endocrinol Metab · March 2010 Adiponectin (APN) has traditionally been viewed as an adipocyte-specific endocrine molecule with cardioprotective effects. Recent studies suggest that APN is also expressed in cardiomyocytes. However, biological significances of this locally produced APN r ... Full text Link to item Cite

Adiponectin: an indispensable molecule in rosiglitazone cardioprotection following myocardial infarction.

Journal Article Circ Res · February 5, 2010 RATIONALE: Patients treated with peroxisome proliferator-activated receptor (PPAR)-gamma agonist manifest favorable metabolic profiles associated with increased plasma adiponectin (APN). However, whether increased APN production as a result of PPAR-gamma a ... Full text Link to item Cite

Dynamic changes in lymphocyte GRK2 levels in cardiac transplant patients: a biomarker for left ventricular function.

Journal Article Clin Transl Sci · February 2010 G protein-coupled receptor kinase 2 (GRK2), which is upregulated in the failing human myocardium, appears to have a role in heart failure (HF) pathogenesis. In peripheral lymphocytes, GRK2 expression has been shown to reflect myocardial levels. This study ... Full text Link to item Cite

β-adrenoceptors in cardiovascular and respiratory diseases

Chapter · January 1, 2010 FUTURE PERSPECTIVES OVERVIEW β-Adrenoceptors (βARs) of which there are three subtypes (β1, β2 and β3) belong to the superfamily of seven transmembrane-spanning receptors or G protein-coupled receptors (GPCRs) and are the bi ... Full text Cite

Induced overexpression of Na+/Ca2+ exchanger transgene: altered myocyte contractility, [Ca2+]i transients, SR Ca2+ contents, and action potential duration.

Journal Article Am J Physiol Heart Circ Physiol · August 2009 We have produced mice in which expression of the rat cardiac Na(+)/Ca(2+) exchanger (NCX1) transgene was switched on when doxycycline was removed from the feed at 5 wk. At 8 to 10 wk, NCX1 expression in induced (Ind) mouse hearts was 2.5-fold higher but pr ... Full text Link to item Cite

An adrenal beta-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo.

Journal Article Proc Natl Acad Sci U S A · April 7, 2009 Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin ... Full text Link to item Cite

Is erythropoietin behind maladaptive anemic heart failure?

Journal Article Am J Physiol Heart Circ Physiol · March 2009 Full text Link to item Cite

Heart failure gene therapy: closer to reality. Professor Walter Koch speaks to Christine Forder, commissioning editor.

Journal Article Future Cardiol · March 2009 Professor Walter Koch is currently a Director at the Center for Translational Medicine and Vice Chairman for Research in the Department of Medicine at Jefferson Medical College, Thomas Jefferson University, PA, USA. Professor Koch started his career as a R ... Full text Link to item Cite

INO-4885 [5,10,15,20-tetra[N-(benzyl-4'-carboxylate)-2-pyridinium]-21H,23H-porphine iron(III) chloride], a peroxynitrite decomposition catalyst, protects the heart against reperfusion injury in mice.

Journal Article J Pharmacol Exp Ther · March 2009 Oxidative/nitrative stress caused by peroxynitrite, the reaction product of superoxide (O2(.-)) and nitric oxide (NO), is the primary cause of myocardial ischemia/reperfusion injury. The present study determined whether INO-4885 [5,10,15,20-tetra[N-(benzyl ... Full text Link to item Cite

AMP-activated protein kinase deficiency enhances myocardial ischemia/reperfusion injury but has minimal effect on the antioxidant/antinitrative protection of adiponectin.

Journal Article Circulation · February 17, 2009 BACKGROUND: Diabetes increases the morbidity/mortality of ischemic heart disease, but the underlying mechanisms are incompletely understood. Deficiency of both AMP-activated protein kinase (AMPK) and adiponectin occurs in diabetes, but whether AMPK is card ... Full text Link to item Cite

Negative regulation of VEGF signaling in human coronary artery endothelial cells by G protein-coupled receptor kinase 5.

Journal Article Clin Transl Sci · February 2009 G protein-coupled receptor kinase 5 (GRK5) is present in endothelial cells (ECs) and has the potential to regulate EC function through seven transmembrane-spanning receptor (7TMR) signaling. Recently, it has been appreciated that GRKs can affect receptor t ... Full text Link to item Cite

Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation--a novel mechanism for the cardioprotective effects of PPAR agonists.

Journal Article Cardiovasc Res · February 1, 2009 AIMS: Hypercholesterolaemia and myeloperoxidase (MPO) overexpression are two well-recognized risk factors for ischaemic heart disease. Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have recently been shown to reduce ischaemic heart ... Full text Link to item Cite

Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure.

Journal Article Circulation · January 6, 2009 BACKGROUND: The upregulation of G protein-coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional beta-adrenergic receptor (betaAR) signaling and cardiac function. The peptide betaARKct, which can inhibit the activation of G ... Full text Link to item Cite

Inhibition of angiotensin II Gq signaling augments beta-adrenergic receptor mediated effects in a renal artery stenosis model of high blood pressure.

Journal Article J Mol Cell Cardiol · January 2009 Chronic ventricular pressure overload states, such as hypertension, and elevated levels of neurohormones (norepinephrine, angiotensin II, endothelin-1) initiate cardiac hypertrophy and dysfunction and share the property of being able to bind to Gq-coupled ... Full text Link to item Cite

Future G protein-coupled receptor targets for treatment of heart failure

Journal Article Current Treatment Options in Cardiovascular Medicine · January 1, 2009 Heart failure (HF) still poses an enormous clinical challenge, as its incidence, morbidity, and mortality rates are continuously rising. G protein-coupled receptors (GPCRs) constitute the most ubiquitous superfamily of plasma membrane receptors and represe ... Full text Cite

[Activation of sterol regulatory element binding protein and its involvement in endothelial cell migration].

Journal Article Zhonghua Bing Li Xue Za Zhi · January 2009 OBJECTIVE: To study the activation of sterol regulatory element binding protein (SREBP) and its critical role in endothelial cell migration. METHODS: Bovine aortic endothelial cells (ECs) were cultured. The expression of SREBP and Cdc42 were determined by ... Link to item Cite

Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha1D-adrenergic receptor constriction.

Journal Article Am J Physiol Heart Circ Physiol · October 2008 G protein-coupled receptor kinase 2 (GRK2) is a serine/theorinine kinase that phosphorylates and desensitizes agonist-bound G protein-coupled receptors. GRK2 is increased in expression and activity in lymphocytes and vascular smooth muscle (VSM) in human h ... Full text Link to item Cite

BMP-2 and FGF-2 synergistically facilitate adoption of a cardiac phenotype in somatic bone marrow c-kit+/Sca-1+ stem cells.

Journal Article Clin Transl Sci · September 2008 The aim of this study was to explore the effect of bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor-2 (FGF-2)- paracrine factors implicated in both cardiac embryogenesis and cardiac repair following myocardial infarction (MI)-on murine bon ... Full text Link to item Cite

Cardiac-restricted overexpression of the A(2A)-adenosine receptor in FVB mice transiently increases contractile performance and rescues the heart failure phenotype in mice overexpressing the A(1)-adenosine receptor.

Journal Article Clin Transl Sci · September 2008 In the heart, adenosine binds to pharmacologically distinct G-protein-coupled receptors (A(1)-R, A(2A)-R, and A(3)-R). While the role of A(1)- and A(3)-Rs in the heart has been clarified, the effect of genetically manipulating the A(2A)-R has not been defi ... Full text Link to item Cite

Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes.

Journal Article Proc Natl Acad Sci U S A · August 26, 2008 G protein-coupled receptor (GPCR) kinases (GRKs) are critical regulators of cellular signaling and function. In cardiomyocytes, GRK2 and GRK5 are two GRKs important for myocardial regulation, and both have been shown to be up-regulated in the dysfunctional ... Full text Link to item Cite

Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism.

Journal Article Cell Cycle · August 15, 2008 Long-chain fatty acids (FA) are the primary energy source utilized by the adult heart. However, during pathological cardiac hypertrophy the fetal gene program is reactivated and glucose becomes the major fuel source metabolized by the heart. Herein we desc ... Full text Link to item Cite

G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure.

Journal Article Circ Res · August 15, 2008 Myocardial G protein-coupled receptor kinase (GRK)2 is a critical regulator of cardiac beta-adrenergic receptor (betaAR) signaling and cardiac function. Its upregulation in heart failure may further depress cardiac function and contribute to mortality in t ... Full text Link to item Cite

Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts.

Journal Article Am J Physiol Heart Circ Physiol · August 2008 Caveolin-3 (Cav3), the primary protein component of caveolae in muscle cells, regulates numerous signaling pathways including insulin receptor signaling and facilitates free fatty acid (FA) uptake by interacting with several FA transport proteins. We previ ... Full text Link to item Cite

Gi/o signaling and its potential role in cardioprotection.

Journal Article Expert Rev Cardiovasc Ther · July 2008 Full text Link to item Cite

Gene therapy in heart failure.

Journal Article Circ Res · June 20, 2008 With increasing knowledge of basic molecular mechanisms governing the development of heart failure (HF), the possibility of specifically targeting key pathological players is evolving. Technology allowing for efficient in vivo transduction of myocardial ti ... Full text Link to item Cite

Adrenal beta-arrestin 1 promotes physiological aldosterone production

Conference Review of Clinical Pharmacology and Pharmacokinetics International Edition · June 19, 2008 Elevated aldosterone levels accompany and aggravate chronic heart failure (HF). Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT 1Rs), G protein coupled ... Cite

A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure.

Journal Article Nat Med · May 2008 Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing o ... Full text Link to item Cite

Exercise promotes angiogenesis and improves beta-adrenergic receptor signalling in the post-ischaemic failing rat heart.

Journal Article Cardiovasc Res · May 1, 2008 AIMS: We investigated whether exercise training could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodelling of the post-myocardial infarction (MI) failing heart. We also explored the contribution of ameliorated beta-adrener ... Full text Link to item Cite

Simultaneous administration of insulin-like growth factor-1 and darbepoetin alfa protects the rat myocardium against myocardial infarction and enhances angiogenesis.

Journal Article Clin Transl Sci · May 2008 Recent studies have shown that insulin growth factor-1 (IGF-1) and either erythropoietin (EPO) or the long-acting EPO analog Darbepoetin alfa (DA) protect the heart against ischemia/reperfusion (I/R) and myocardial infarction (MI). The present study examin ... Full text Link to item Cite

Cardiac-restricted expression of the carboxyl-terminal fragment of GRK3 Uncovers Distinct Functions of GRK3 in regulation of cardiac contractility and growth: GRK3 controls cardiac alpha1-adrenergic receptor responsiveness.

Journal Article J Biol Chem · April 18, 2008 G protein-coupled receptor kinase-2 and -3 (GRK2 and GRK3) in cardiac myocytes catalyze phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by their carboxyl-terminal pleckstrin homology domain. Altho ... Full text Link to item Cite

Endothelial S100A1 modulates vascular function via nitric oxide.

Journal Article Circ Res · April 11, 2008 S100A1, a Ca(2+)-binding protein of the EF-hand type, is known to modulate sarcoplasmic reticulum Ca(2+) handling in skeletal muscle and cardiomyocytes. Recently, S100A1 has been shown to be expressed in endothelial cells (ECs). Because intracellular Ca(2+ ... Full text Link to item Cite

Targeted inhibition of cardiomyocyte Gi signaling enhances susceptibility to apoptotic cell death in response to ischemic stress.

Journal Article Circulation · March 18, 2008 BACKGROUND: A salient characteristic of dysfunctional myocardium progressing to heart failure is an upregulation of the adenylyl cyclase inhibitory guanine nucleotide (G) protein alpha subunit, G alpha(i2). It has not been determined conclusively whether i ... Full text Link to item Cite

Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active G alpha o* protein.

Journal Article Am J Physiol Heart Circ Physiol · March 2008 In contrast to the other heterotrimeric GTP-binding proteins (G proteins) Gs and Gi, the functional role of G o is still poorly defined. To investigate the role of G alpha o in the heart, we generated transgenic mice with cardiac-specific expression of a c ... Full text Link to item Cite

Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity.

Journal Article Mol Ther · February 2008 We recently reported that the upregulation of adrenal G protein-coupled receptor kinase-2 (GRK2) causes enhanced catecholamine (CA) secretion by desensitizing sympatho-inhibitory alpha (2)-adrenergic receptors (alpha (2)ARs) of chromaffin cells, and thereb ... Full text Link to item Cite

AUTONOMIC PHARMACOLOGY

Chapter · January 1, 2008 Full text Cite

Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation.

Journal Article Trends Mol Med · December 2007 Chronic heart failure (HF) is characterized by sympathetic hyperactivity reflected by increased circulating catecholamines (CAs), which contributes significantly to its morbidity and mortality. Therefore, sympatholytic treatments, that is, treatments that ... Full text Link to item Cite

Recent findings into the potential of gene therapy to reverse heart failure.

Journal Article Expert Opin Biol Ther · December 2007 The incidence of heart failure (HF) is ever growing and the mortality of HF patients is similar to patients suffering from cancer disease. The central clinical problem is a lack of therapies to target the underlying molecular defects that lead to chronic v ... Full text Link to item Cite

Calcineurin inhibition normalizes beta-adrenergic responsiveness in the spontaneously hypertensive rat.

Journal Article Am J Physiol Heart Circ Physiol · November 2007 Calcineurin, a Ca(2+)-regulated protein phosphatase, links myocardial Ca(2+) signaling with hypertrophic gene transcription. Calcineurin abundance increases in pressure-overload hypertrophy and may reduce agonist-mediated phospholamban (PLB) phosphorylatio ... Full text Link to item Cite

Exercise training and beta-blocker treatment ameliorate age-dependent impairment of beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation.

Journal Article Am J Physiol Heart Circ Physiol · September 2007 Cardiac beta-adrenergic receptor (beta-AR) signaling and left ventricular (LV) responses to beta-AR stimulation are impaired with aging. It is shown that exercise and beta-AR blockade have a favorable effect on cardiac and vascular beta-AR signaling in sev ... Full text Link to item Cite

Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function.

Journal Article Mol Pharmacol · September 2007 The closely related G protein-coupled receptor kinases GRK2 and GRK3 are both expressed in cardiac myocytes. Although GRK2 has been extensively investigated in terms of regulation of cardiac beta-adrenergic receptors, the substrate specificities of the two ... Full text Link to item Cite

Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia.

Journal Article Proc Natl Acad Sci U S A · August 7, 2007 Intimal hyperplasia (IH) and restenosis limit the long-term utility of bypass surgery and angioplasty due to pathological proliferation and migration of vascular smooth muscle cells (VSMCs) into the intima of treated vessels. Consequently, much attention h ... Full text Link to item Cite

S100A1: a novel inotropic regulator of cardiac performance. Transition from molecular physiology to pathophysiological relevance.

Journal Article Am J Physiol Regul Integr Comp Physiol · August 2007 Here we review the considerable body of evidence that has accumulated to support the notion of S100A1, a cardiac-specific Ca(2+)-sensor protein of the EF-hand type, as a physiological regulator of excitation-contraction coupling and inotropic reserve mecha ... Full text Link to item Cite

Molecular scaffolds regulate bidirectional crosstalk between Wnt and classical seven-transmembrane-domain receptor signaling pathways.

Journal Article Sci STKE · July 31, 2007 Signaling downstream of classical seven-transmembrane domain receptors (7TMRs) had generally been thought to recruit factors that are in large part separate from those recruited by atypical 7TMRs, such as Frizzleds (Fzs), receptors for the Wnt family of gl ... Full text Link to item Cite

Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart.

Journal Article Am J Physiol Heart Circ Physiol · July 2007 Recent studies from our lab and others have shown that the hematopoietic cytokine erythropoietin (EPO) can protect the heart from ischemic damage in a red blood cell-independent manner. Here we examined any protective effects of the long-acting EPO analog ... Full text Link to item Cite

Nitrative thioredoxin inactivation as a cause of enhanced myocardial ischemia/reperfusion injury in the aging heart.

Journal Article Free Radic Biol Med · July 1, 2007 Several recent studies have demonstrated that thioredoxin (Trx) is an important antiapoptotic/cytoprotective molecule. The present study was designed to determine whether Trx activity is altered in the aging heart in a way that may contribute to increased ... Full text Link to item Cite

Targeting myocardial beta-adrenergic receptor signaling and calcium cycling for heart failure gene therapy.

Journal Article J Card Fail · June 2007 Heart failure (HF) is a leading cause of morbidity and mortality in Western countries and projections reveal that HF incidence in the coming years will rise significantly because of an aging population. Pharmacologic therapy has considerably improved HF tr ... Full text Link to item Cite

Ark1-directed β2-adrenergic receptor coupling to Gi signaling leads to heart failure

Conference Journal of Molecular and Cellular Cardiology · June 2007 Full text Cite

Ca2+ -dependent interaction of S100A1 with F1-ATPase leads to an increased ATP content in cardiomyocytes.

Journal Article Mol Cell Biol · June 2007 S100A1, a Ca(2+)-sensing protein of the EF-hand family that is expressed predominantly in cardiac muscle, plays a pivotal role in cardiac contractility in vitro and in vivo. It has recently been demonstrated that by restoring Ca(2+) homeostasis, S100A1 was ... Full text Link to item Cite

657 Dual S100A1/BARKct adenoviral gene transfer in ventricular cardiomyocytes

Conference European Journal of Heart Failure Supplements · June 2007 Full text Cite

Developing strategies to link basic cardiovascular sciences with clinical drug development: another opportunity for translational sciences.

Journal Article Clin Pharmacol Ther · June 2007 Driven, at least in part, by the National Institutes of Health roadmap, an increasing number of studies has bridged the chasm between observations in the basic research laboratory and the clinical bedside. These studies have been an integral part in "trans ... Full text Link to item Cite

Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue.

Journal Article Circulation · May 15, 2007 BACKGROUND: The incidence of heart failure is ever-growing, and it is urgent to develop improved treatments. An attractive approach is gene therapy; however, the clinical barrier has yet to be broken because of several issues, including the lack of an idea ... Full text Link to item Cite

Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.

Journal Article Cell · May 4, 2007 beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric ... Full text Link to item Cite

Prior exercise improves age-dependent vascular endothelial growth factor downregulation and angiogenesis responses to hind-limb ischemia in old rats.

Journal Article J Gerontol A Biol Sci Med Sci · May 2007 Downregulation of hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) are shown to be involved in age-dependent impairment of angiogenesis. In this study, we explore whether prior exercise is able to affect these molecular patt ... Full text Link to item Cite

A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction.

Journal Article Circulation · May 1, 2007 BACKGROUND: It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine-adenosine receptor (AR) pathways in hearts with left ventricular dilation ... Full text Link to item Cite

Lymphocyte G-protein-coupled receptor kinase-2 is upregulated in patients with Alzheimer's disease.

Journal Article Neurosci Lett · March 30, 2007 Alterations in signal transduction pathway of G-protein-coupled receptors (GPCRs) have been found in the cerebrocortex and in the peripheral cultured tissues of patients with Alzheimer's disease (AD). The G-protein-coupled receptor kinase-2 (GRK2) plays an ... Full text Link to item Cite

Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress.

Journal Article Circulation · March 20, 2007 BACKGROUND: Several clinical studies have demonstrated that levels of adiponectin are significantly reduced in patients with type 2 diabetes and that adiponectin levels are inversely related to the risk of myocardial ischemia. The present study was designe ... Full text Link to item Cite

Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure.

Journal Article Nat Med · March 2007 Cardiac overstimulation by the sympathetic nervous system (SNS) is a salient characteristic of heart failure, reflected by elevated circulating levels of catecholamines. The success of beta-adrenergic receptor (betaAR) antagonists in heart failure argues f ... Full text Link to item Cite

S100A1 decreases calcium spark frequency and alters their spatial characteristics in permeabilized adult ventricular cardiomyocytes.

Journal Article Cell Calcium · February 2007 S100A1, a Ca2+-sensor protein of the EF-hand type, exerts positive inotropic effects in the heart via enhanced cardiac ryanodine receptor (RyR2) activity. Here we report that S100A1 protein (0.1microM) interacts with the RyR2 in resting permeabilized cardi ... Full text Link to item Cite

Beta blocker specificity: a building block toward personalized medicine.

Journal Article J Clin Invest · January 2007 Drugs known as beta blockers, which antagonize the beta-adrenergic receptor (beta-AR), are an important component of the treatment regimen for chronic heart failure (HF). However, a significant body of evidence indicates that genetic heterogeneity at the l ... Full text Link to item Cite

G protein-coupled receptor kinases and hypertension: A review of disease mechanisms

Journal Article High Blood Pressure and Cardiovascular Prevention · December 1, 2006 The understanding of molecular mechanisms of complex physiological phenomena, such as cardiac contractile function or blood pressure homeostasis, has generated the need for a new generation of scientists who must be able to conjugate intrinsic biological m ... Full text Cite

Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function.

Journal Article Circulation · November 21, 2006 BACKGROUND: Both the A1- and A3-adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A1-AR and A3-AR is associated with changes in the cardiac phenotype. To evaluate th ... Full text Link to item Cite

S100A1 gene transfer in myocardium.

Journal Article Eur J Med Res · October 27, 2006 S100A1, a Ca superset2+-binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been shown to enhance cardiac contractile performance by regulating both sarcoplasmic reticulum (SR) Ca superset2+-handling and myofibrill ... Link to item Cite

Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling.

Journal Article Circ Res · October 27, 2006 G-protein receptor kinase 2 (GRK2) is 1 of 7 mammalian GRKs that phosphorylate ligand-bound 7-transmembrane receptors, causing receptor uncoupling from G proteins and potentially activating non-G-protein signaling pathways. GRK2 is unique among members of ... Full text Link to item Cite

Thioredoxin reduces post-ischemic myocardial apoptosis by reducing oxidative/nitrative stress.

Journal Article Br J Pharmacol · October 2006 BACKGROUND AND PURPOSE: Thioredoxin (Trx) is an oxidoreductase that prevents free radical-induced cell death in cultured cells. Here we assessed the mechanism(s) underlying the cardioprotective effects of Trx in vivo. EXPERIMENTAL APPROACH: The effects of ... Full text Link to item Cite

Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis.

Journal Article Circulation · September 26, 2006 BACKGROUND: Intracellular proteins involved in oxidative stress and apoptosis are nitrated in diseased tissues but not in normal tissues; definitive evidence to support a causative link between a specific protein that is nitratively modified with tissue in ... Full text Link to item Cite

Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction.

Journal Article Circulation · September 19, 2006 BACKGROUND: Diminished cardiac S100A1 protein levels are characteristic of ischemic and dilated human cardiomyopathy. Because S100A1 has recently been identified as a Ca2+-dependent inotropic factor in the heart, this study sought to explore the pathophysi ... Full text Link to item Cite

Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure.

Journal Article Circulation · August 8, 2006 BACKGROUND: The conventional protein kinase C (PKC) isoform alpha functions as a proximal regulator of Ca2+ handling in cardiac myocytes. Deletion of PKCalpha in the mouse results in augmented sarcoplasmic reticulum Ca2+ loading, enhanced Ca2+ transients, ... Full text Link to item Cite

Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress.

Journal Article J Pharmacol Exp Ther · August 2006 The present study provides evidence that inducible nitric-oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic beta-adrenergic receptor (AR) stimulation-induced cardiac damage. In mice, 14 days of isoproterenol (ISO) stimulation ... Full text Link to item Cite

Alpha2-adrenergic receptor subtype-specific activation of NF-kappaB in PC12 cells.

Journal Article Neurosci Lett · July 24, 2006 In the present study we sought to investigate the signal transduction mechanisms that underlie the alpha2-adrenergic receptor (AR)-induced, subtype-specific neuronal differentiation of PC12 cells. Alpha2-ARs induced NF-kappaB transcriptional activity and p ... Full text Link to item Cite

Role of adrenal GRK2 in heart failure

Conference Review of Clinical Pharmacology and Pharmacokinetics International Edition · June 6, 2006 Heart failure (HF) is characterized by sympathetic hyperactivity and enhanced circulating catecholamines (CA's). CA's stimulating cardiac function are norepinephrine released from cardiac sympathetic nerves and circulating CA's secreted from the adrenal gl ... Cite

Lymphocyte levels of GRK2 (betaARK1) mirror changes in the LVAD-supported failing human heart: lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading.

Journal Article J Card Fail · June 2006 BACKGROUND: In human heart failure, increased expression of G protein-coupled receptor kinases (GRKs) causes the loss of beta-adrenergic receptor (betaAR) signaling and function. Mechanical unloading with a left ventricular assist device (LVAD) promotes re ... Full text Link to item Cite

Galphaq and its Aktions.

Journal Article J Mol Cell Cardiol · May 2006 Full text Link to item Cite

S100A1 increases the gain of excitation-contraction coupling in isolated rabbit ventricular cardiomyocytes.

Journal Article J Mol Cell Cardiol · December 2005 The effect of S100A1 protein on cardiac excitation-contraction (E-C) coupling was studied using recombinant human S100A1 protein (0.01-10 microM) introduced into single rabbit ventricular cardiomyocytes via a patch pipette. Voltage clamp experiments (20 de ... Full text Link to item Cite

S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction.

Journal Article Mol Ther · December 2005 Myocardial infarction (MI) represents an enormous clinical challenge as loss of myocardium due to ischemic injury is associated with compromised left ventricular (LV) function often leading to acute cardiac decompensation or chronic heart failure. S100A1 w ... Full text Link to item Cite

A Gbetagamma inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

Journal Article J Thorac Cardiovasc Surg · December 2005 OBJECTIVE: Approximately 50% of aortocoronary saphenous vein grafts are occluded 10 years after coronary revascularization surgery. Intimal hyperplasia, a critical component in saphenous vein graft failure, is defined by vascular smooth muscle cell prolife ... Full text Link to item Cite

Ischemic neoangiogenesis enhanced by beta2-adrenergic receptor overexpression: a novel role for the endothelial adrenergic system.

Journal Article Circ Res · November 25, 2005 Beta2-adrenergic receptors (beta2ARs) are widely expressed, although their physiological relevance in many tissues is not yet fully understood. In vascular endothelial cells, they regulate NO release and vessel tone. Here we provide novel evidence that bet ... Full text Link to item Cite

Acute ischemic cardiac dysfunction is attenuated via gene transfer of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1).

Journal Article The journal of gene medicine · September 2005 Acute myocardial ischemia is a critical adverse effect potentially occurring during cardiac procedures. A peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1), betaARKct, has been successful in rescuing chronic myocardial ischemia. The prese ... Full text Cite

Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure.

Journal Article Eur Heart J · September 2005 AIMS: The G protein-coupled receptor kinase-2 (GRK2 or beta-ARK1) regulates beta-adrenergic receptors (beta-ARs) in the heart, and its cardiac expression is elevated in human heart failure (HF). We sought to determine whether myocardial levels and activity ... Full text Link to item Cite

Reduction of vascular intimal-medial hyperplasia in polytetrafluoroethylene arteriovenous grafts via expression of an inhibitor of G protein signaling.

Journal Article Ann Vasc Surg · September 2005 Polytetrafluoroethylene (PTFE) arteriovenous (AV) grafts are performed routinely for vascular access. The limited life span of PTFE grafts is a major cause of morbidity. Graft failure is attributed to venous outflow tract vascular smooth muscle (VSM) hyper ... Full text Link to item Cite

Improved myocardial beta-adrenergic responsiveness and signaling with exercise training in hypertension.

Journal Article Circulation · June 28, 2005 BACKGROUND: Cardiac responses to beta-adrenergic receptor stimulation are depressed with pressure overload-induced cardiac hypertrophy. We investigated whether exercise training could modify beta-adrenergic receptor responsiveness in a model of spontaneous ... Full text Link to item Cite

Exercise Training Increases Beta Adrenergic Responsiveness In Hypertension

Conference Medicine & Science in Sports & Exercise · May 2005 Full text Cite

Catheter-mediated subselective intracoronary gene delivery to the rabbit heart: introduction of a novel method.

Journal Article J Gene Med · May 2005 BACKGROUND: Recent studies suggest that gene therapy using replication-deficient adenoviruses will benefit treatment of cardiovascular diseases including heart failure. A persistent hurdle is the effective and reproducible delivery of a transgene to the my ... Full text Link to item Cite

G protein-coupled receptor kinase 5 diminishes injury-induced vascular neointima formation

Conference ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY · May 1, 2005 Link to item Cite

Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.

Journal Article Circulation · February 8, 2005 BACKGROUND: Heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1). Our previous studies have shown that inhibition of betaARK1 with the use of the ... Full text Open Access Link to item Cite

The Implications of 'Psychological Injuries' for Clinical Psychology Training Programs.

Journal Article Canadian Psychology / Psychologie canadienne · February 2005 Full text Cite

Empirical Limits for the Forensic Assessment of PTSD Litigants.

Journal Article Law and Human Behavior · February 2005 Full text Cite

Distinct subcellular location of the Ca2+-binding protein S100A1 differentially modulates Ca2+-cycling in ventricular rat cardiomyocytes.

Journal Article J Cell Sci · January 15, 2005 Calcium is a key regulator of cardiac function and is modulated through the Ca2+-sensor protein S100A1. S100 proteins are considered to exert both intracellular and extracellular functions on their target cells. Here we report the impact of an increased in ... Full text Link to item Cite

Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion.

Journal Article Circulation · January 4, 2005 BACKGROUND: Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent as well as caspase-independent cell death. However, the role of Omi/HtrA2 in the apoptotic cell death that occurs in vivo under pathological conditions rema ... Full text Link to item Cite

Gene therapy in acute myocardial infarction

Conference CIRCULATION · 2005 Cite

Gene therapy approaches to cardiovascular disease.

Journal Article Methods Mol Med · 2005 The potential of enhanced cardiovascular function via gene therapy has aroused extensive interest. Both viral and nonviral vectors have shown promise in the realm of cardiovascular gene therapy. Modification of vectors or addition of further transgenes to ... Full text Link to item Cite

Cardiac gene delivery using DNA-adenoviral constructs.

Journal Article Methods Mol Med · 2005 In view of the limitations of current cardiac gene transfer techniques by direct myocardial injection, or via the coronary vasculature, we have been attempting to develop potentially clinically applicable methods. Selective catheterization of the coronary ... Link to item Cite

Cardiac adenoviral S100A1 gene delivery rescues failing myocardium.

Journal Article J Clin Invest · December 2004 Cardiac-restricted overexpression of the Ca2+-binding protein S100A1 has been shown to lead to increased myocardial contractile performance in vitro and in vivo. Since decreased cardiac expression of S100A1 is a characteristic of heart failure, we tested t ... Full text Link to item Cite

Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

Journal Article Journal of Clinical Investigation · December 1, 2004 Full text Cite

beta2 adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery.

Journal Article Eur J Cardiothorac Surg · December 2004 OBJECTIVE: Heart surgery is associated with impairment of the myocardial beta-adrenoceptor (betaAR) system. Effective therapies for post-operative ventricular dysfunction are limited. Prolonged inotrope exposure is associated with further betaAR down-regul ... Full text Link to item Cite

Dose dependent effects of cardiac beta2 adrenoceptor gene therapy.

Journal Article J Surg Res · November 2004 BACKGROUND: Adenoviral-mediated gene transfer during cardiopulmonary bypass (CPB) achieves efficient myocardial transgene expression. The optimal vector dose required to produce not only increased beta adrenoceptor (betaAR) density but, more importantly, e ... Full text Link to item Cite

Catheter-mediated delivery of adenoviral vectors expressing beta-adrenergic receptor kinase C-terminus inhibits intimal hyperplasia and luminal stenosis in rabbit iliac arteries.

Journal Article J Gene Med · October 2004 BACKGROUND: Previous studies have shown that incubation of balloon-injured rat carotid arteries with adenoviral vectors encoding the carboxyl terminus of the beta-adrenergic receptor kinase (Ad2/betaARKct) for 30 min reduces neointima formation. However, i ... Full text Link to item Cite

Gene delivery approaches to heart failure treatment.

Journal Article Expert Opin Biol Ther · September 2004 Heart failure remains a leading cause of worldwide morbidity and mortality. Despite recent advances in treatment and our increasing knowledge of pathophysiology and the molecular derangements involved in the failing heart, our ability to affect the underly ... Full text Link to item Cite

Cardioprotective effects of thioredoxin in myocardial ischemia and reperfusion: role of S-nitrosation [corrected].

Journal Article Proc Natl Acad Sci U S A · August 3, 2004 Apoptosis contributes to myocardial ischemia/reperfusion (MI/R) injury, and both thioredoxin (Trx) and nitric oxide have been shown to exert antiapoptotic effects in vitro. Recent evidence suggests that this particular action of Trx requires S-nitrosation ... Full text Link to item Cite

Genetic and phenotypic targeting of beta-adrenergic signaling in heart failure.

Conference Mol Cell Biochem · August 2004 Heart failure is a leading cause of hospitalization worldwide. No major significant improvements in prognosis have been achieved for heart failure over the last several decades despite advances in disease management. Heart failure itself represents a final ... Link to item Cite

Molecular restoration of beta-adrenergic receptor signaling improves contractile function of failing hearts.

Journal Article Trends Cardiovasc Med · August 2004 beta-adrenergic receptor (betaAR) antagonists, or beta blockers, are now a part of the standard therapeutic arsenal in the medical management of chronic heart failure (HF). Conversely, betaAR stimulation remains the most efficient way to enhance cardiac co ... Full text Link to item Cite

Cardioprotective effects of erythropoietin: A journey from the bedside back to the bench

Journal Article Drugs of the Future · August 1, 2004 Recombinant human erythropoietin (rHuEPO) has been used for 15 years for the clinical management of anemia. Mitigation of chronic anemia has led to improved cardiac function, which served as a clinical indication for chronic EPO therapy in renal failure an ... Full text Cite

Genetic manipulation of myocardial beta-adrenergic receptor activation and desensitization.

Journal Article J Mol Cell Cardiol · July 2004 Heart failure (HF) represents one of the leading causes of morbidity and mortality in developed nations today. Although this disease process represents a final common endpoint for several entities, including hypertension, coronary artery disease, and cardi ... Full text Link to item Cite

Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts.

Journal Article J Biol Chem · May 14, 2004 Erythropoietin has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia. In this study, we evaluated the in vivo protective potential of erythropoietin in the reperfused rabbit ... Full text Link to item Cite

Calcium channel function and regulation in beta 1- and beta 2-adrenoceptor transgenic mice.

Journal Article Naunyn Schmiedebergs Arch Pharmacol · May 2004 Cardiac effects of catecholamines on the L-type calcium channel depend on beta-adrenoceptor subtype (beta(1)- vs. beta(2)-adrenoceptor). Chronic overexpression of these receptors leads to hypertrophy and early death at moderate (beta(1)) or excessive (beta ... Full text Link to item Cite

G protein-coupled receptor internalization signaling is required for cardioprotection in ischemic preconditioning.

Journal Article Circ Res · April 30, 2004 The present study is designed to explore the role of G protein-coupled receptors (GPCRs) in the protection afforded by ischemic preconditioning (PC). We used TG mice with cardiac-specific overexpression of a Gbetagamma-sequestering peptide, betaARKct (TG b ... Full text Link to item Cite

Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts.

Journal Article Circulation · April 6, 2004 BACKGROUND: Failing human myocardium is characterized by an attenuated contractile response to beta-adrenergic receptor (betaAR) stimulation due to changes in this signaling cascade, including increased expression and activity of the beta-adrenergic recept ... Full text Link to item Cite

S100A1 gene transfer: a strategy to strengthen engineered cardiac grafts.

Journal Article J Gene Med · April 2004 BACKGROUND: Cardiac tissue replacement therapy, although a promising novel approach for the potential treatment of heart failure, still suffers from insufficient contractile support to the failing myocardium. Here, we explore a strategy to improve contract ... Full text Link to item Cite

Viral-based myocardial gene therapy approaches to alter cardiac function.

Journal Article Annu Rev Physiol · 2004 In recent years there has been a rapid expansion in our understanding of the molecular biology that underpins human physiology. In the heart, elegant molecular pathways have been elucidated, and derangements in these pathways have been identified as factor ... Full text Link to item Cite

Gene therapy for heart failure.

Conference Ann Med · 2004 Despite our continued advances in the management of coronary artery disease, there have been no significant reductions in the morbidity or mortality related to end-stage heart failure. The syndrome of heart failure represents a common endpoint for several ... Full text Link to item Cite

The adrenergic pathway and heart failure.

Journal Article Recent Prog Horm Res · 2004 Heart failure represents the endpoint to many triggering cardiovascular pathologies. However, there are molecular and biochemical features that remain common to the failing heart, despite the varying etiologies. Principal among these is heightened activati ... Full text Link to item Cite

In vivo adenoviral-mediated gene transfer of the beta ARKct to study the role of G beta gamma in arterial restenosis.

Journal Article Methods Mol Biol · 2004 A large body of in vitro studies has helped to elucidate intracellular pathways that lead to mitogenic signaling in vascular smooth muscle (VSM) cells. However, a limitation of these studies is that they fail to test the in vivo physiological significance ... Full text Link to item Cite

Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia.

Journal Article J Thorac Cardiovasc Surg · January 2004 OBJECTIVE: More than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is an initial, critical step in the progression toward occlusion. To date, no clinically relevant large animal models of aortocoronary ... Full text Link to item Cite

Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through beta 2-adrenoceptors.

Journal Article Proc Natl Acad Sci U S A · November 25, 2003 Two subtypes of beta-adrenoceptors, beta 1 and beta 2, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human beta 2-adrenoceptor ... Full text Link to item Cite

Extracellular S100A1 protein inhibits apoptosis in ventricular cardiomyocytes via activation of the extracellular signal-regulated protein kinase 1/2 (ERK1/2).

Journal Article The Journal of biological chemistry · November 2003 S100A1 is a Ca2+-binding protein of the EF-hand type that belongs to the S100 protein family. It is specifically expressed in the myocardium at high levels and is considered to be an important regulator of cardiac contractility. Because the S100A1 protein ... Full text Cite

Cardiac hypertrophy and altered beta-adrenergic signaling in transgenic mice that express the amino terminus of beta-ARK1.

Journal Article Am J Physiol Heart Circ Physiol · November 2003 The G protein-coupled receptor (GPCR) kinase beta-adrenergic receptor (beta-AR) kinase-1 (beta-ARK1) is elevated during heart failure; however, its role is not fully understood. Beta-ARK1 contains several domains that are capable of protein-protein interac ... Full text Link to item Cite

Home surveillance program prevents interstage mortality after the Norwood procedure.

Journal Article J Thorac Cardiovasc Surg · November 2003 OBJECTIVE: To determine whether early identification of physiologic variances associated with interstage death would reduce mortality, we developed a home surveillance program. METHODS: Patients discharged before initiation of home surveillance (group A, n ... Full text Link to item Cite

Differential myocardial gene expression in the development and rescue of murine heart failure.

Journal Article Physiol Genomics · October 17, 2003 Numerous murine models of heart failure (HF) have been described, many of which develop progressive deterioration of cardiac function. We have recently demonstrated that several of these can be "rescued" or prevented by transgenic cardiac expression of a p ... Full text Link to item Cite

The beta-adrenergic receptor kinase in heart failure.

Journal Article J Mol Cell Cardiol · October 2003 Heart failure (HF) remains a significant and increasing cause of worldwide morbidity and mortality. HF is less a disease than a common clinical endpoint resulting from diverse, but often co-existing etiologies-including hypertension, coronary artery diseas ... Full text Link to item Cite

A novel protective effect of erythropoietin in the infarcted heart.

Journal Article J Clin Invest · October 2003 Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit an ... Full text Link to item Cite

Vascular rarefaction in peripheral skeletal muscle after experimental heart failure.

Journal Article Am J Physiol Heart Circ Physiol · October 2003 A decrease in vascular density in peripheral skeletal muscle has been associated with exercise intolerance in humans with congestive heart failure (CHF). The purpose of this study was to determine whether CHF results in a reduction in vascular density in p ... Full text Link to item Cite

Targeting Gbetagamma signaling to inhibit prostate tumor formation and growth.

Journal Article J Biol Chem · September 26, 2003 Prostate cancer starts as androgen-dependent malignancy and responds initially to androgen ablative therapy. Beneficial effects of androgen ablation, however, are often temporary and the cancer reappears as androgen-independent tumor, suggesting the existe ... Full text Link to item Cite

Transgenic overexpression of the Ca2+-binding protein S100A1 in the heart leads to increased in vivo myocardial contractile performance.

Journal Article J Biol Chem · September 5, 2003 S100A1, a Ca2+-sensing protein of the EF-hand family, is most highly expressed in myocardial tissue, and cardiac S100A1 overexpression in vitro has been shown to enhance myocyte contractile properties. To study the physiological consequences of S100A1 in v ... Full text Link to item Cite

Phosphorylation of G protein-coupled receptors: GPCR kinases in heart disease.

Journal Article Mol Interv · August 2003 In the heart, beta -adrenergic receptors (beta ARs), members of the superfamily of G protein-coupled receptors (GPCRs), modulate cardiac responses to catecholamines. beta AR signaling, which is compromised in many cardiac diseases (e.g., congestive heart f ... Full text Link to item Cite

Sealing the leak, healing the heart.

Journal Article Nat Med · August 2003 Full text Link to item Cite

Catheter-based intracoronary myocardial adenoviral gene delivery: importance of intraluminal seal and infusion flow rate.

Journal Article Mol Ther · August 2003 Although percutaneous, adenoviral-mediated intracoronary gene delivery to the heart has been demonstrated in some species, consistent and safe methodology is needed before clinical applicability is possible. In this study, we examine the effects of alterin ... Full text Link to item Cite

Gene interventions in the beta-adrenergic system for treating heart failure.

Journal Article Semin Thorac Cardiovasc Surg · July 2003 Cardiovascular disease accounts for nearly 40% of all deaths annually in this country. Prevention management and advances in medical treatments have dramatically reduced the overall mortality rate due to heart disease. However, death due to chronic heart f ... Full text Link to item Cite

Differential gene expression and genomic patient stratification following left ventricular assist device support.

Journal Article J Am Coll Cardiol · April 2, 2003 OBJECTIVES: We sought to determine whether mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in significant changes in overall left ventricular gene expression. BACKGROUND: Mechanical circulatory support b ... Full text Link to item Cite

Transgenic mice targeting the heart unveil G protein-coupled receptor kinases as therapeutic targets.

Journal Article Assay Drug Dev Technol · April 2003 GRKs critically regulate betaAR signaling via receptor phosphorylation and the triggering of desensitization. In the heart, betaARs control the chronotropic, lusitropic, and inotropic responses to the catecholamine neurotransmitters, norepinephrine and epi ... Full text Link to item Cite

Overexpression of wild-type Galpha(i)-2 suppresses beta-adrenergic signaling in cardiac myocytes.

Journal Article FASEB J · March 2003 The role of Galpha(i)-2 overexpression in desensitization of beta-adrenergic signaling in heart failure is controversial. An adenovirus-based approach was used to investigate whether overexpression of Galpha(i)-2 impairs beta-adrenergic stimulation of aden ... Full text Link to item Cite

Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy.

Journal Article Am J Physiol Heart Circ Physiol · February 2003 Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by varying degrees of ventricular hypertrophy and myofibrillar disarray. Mutations in cardiac contractile proteins cause HCM. However, there is an unexplained wide va ... Full text Link to item Cite

Gβγ-dependent signaling pathway in ischemic preconditioning:: A role for endosomal signaling

Conference JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY · 2003 Cite

Erythropoietin augments cardiomyocyte survival and left ventricular function after hypoxia

Conference JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY · 2003 Cite

A porcine model of intimal-medial hyperplasia in polytetrafluoroethylene arteriovenous grafts.

Journal Article J Vasc Access · 2003 PURPOSE: Vascular access polytetrafluoroethylene (PTFE) graft failure is a major cause of morbidity in the hemodialysis population. The most common cause of graft failure is thrombosis secondary to stenosis at the venous outflow tract. Venous outflow steno ... Link to item Cite

Gene transfer of beta-adrenergic signaling components for heart failure.

Journal Article J Card Fail · December 2002 Heart failure represents one of the leading causes for morbidity and mortality in this country. Despite advances in clinical management, no significant improvements in prognosis have been achieved. Heart failure itself represents a final common endpoint fo ... Full text Link to item Cite

Heterotopic transplantation as a model to study functional recovery of unloaded failing hearts.

Journal Article The Journal of thoracic and cardiovascular surgery · December 2002 ObjectivesRecent studies have demonstrated cardiac improvement in patients supported with a ventricular assist device, suggesting that reverse remodeling and myocardial recovery are possible. We developed an animal model of cardiac unloading by ad ... Full text Cite

Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature.

Journal Article Hypertension (Dallas, Tex. : 1979) · November 2002 The Gq-coupled receptor-signaling pathway has been implicated in the cardiac hypertrophic response to stress, but little is actually known about the contributions of Gq signaling in either the heart or the vasculature. Therefore, we developed a line of tra ... Full text Cite

Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated beta-adrenergic signaling modulation.

Journal Article European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery · November 2002 ObjectivesReperfusion after myocardial ischemia goes together with alteration of the beta-adrenergic (betaAR) signaling. Especially the level and catalytic activity of beta AR kinase (betaARK1) are increased. We hypothesized that myocardial expres ... Full text Cite

Beta-adrenergic receptor-mediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal-regulated kinases.

Journal Article J Biol Chem · August 30, 2002 Cardiac hypertrophy often leads to heart failure and is associated with abnormal myocardial adrenergic signaling. This enlargement of myocardial mass can involve not only an increase in cardiomyocyte size, but increased proliferation of cardiac fibroblasts ... Full text Link to item Cite

Selective inhibition of heterotrimeric Gs signaling. Targeting the receptor-G protein interface using a peptide minigene encoding the Galpha(s) carboxyl terminus.

Journal Article J Biol Chem · August 9, 2002 The blockade of heptahelical receptor coupling to heterotrimeric G proteins by the expression of peptides derived from G protein Galpha subunits represents a novel means of simultaneously inhibiting signals arising from multiple receptors that share a comm ... Full text Link to item Cite

Beta(2)-adrenergic receptor gene delivery to the endothelium corrects impaired adrenergic vasorelaxation in hypertension.

Journal Article Circulation · July 16, 2002 BACKGROUND: Impaired beta-adrenergic receptor (AR)-mediated vasorelaxation in hypertension plays a role in increased peripheral vascular resistance and blood pressure. Because the beta(2)AR is the most abundant vascular AR subtype, we sought to enhance bet ... Full text Link to item Cite

Myocardial gene transfer and overexpression of beta2-adrenergic receptors potentiates the functional recovery of unloaded failing hearts.

Journal Article Circulation · July 2, 2002 BACKGROUND: Mechanical assistance of the failing left ventricle (LV) can lead to functional recovery after a period of unloading, including restoration of beta-adrenergic receptor (betaAR) inotropic reserve. We tested whether prolonged LV unloading of fail ... Full text Link to item Cite

Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice.

Journal Article Mol Cell Biol · July 2002 Nhlh1 is a basic helix-loop-helix transcription factor whose expression is restricted to the nervous system and which may play a role in neuronal differentiation. To directly study Nhlh1 function, we generated null mice. Homozygous mutant mice were predisp ... Full text Link to item Cite

Inhibition of betaARK1 restores impaired biochemical beta-adrenergic receptor responsiveness but does not rescue CREB(A133) induced cardiomyopathy.

Journal Article J Mol Cell Cardiol · June 2002 The myocardial beta-adrenergic receptor (betaAR) system plays a key role in dysfunctional signaling and physiology of the failing heart. Recently we described a murine model of dilated cardiomyopathy (DCM) produced by cardiac-specific expression of a domin ... Full text Link to item Cite

Specific beta(2)AR blocker ICI 118,551 actively decreases contraction through a G(i)-coupled form of the beta(2)AR in myocytes from failing human heart.

Journal Article Circulation · May 28, 2002 BACKGROUND: We have observed direct (noncatecholamine-blocking) negative inotropic effects of the selective beta(2)-adrenoceptor (AR) antagonist ICI 118,551 in myocytes from failing human ventricle. In this study we characterize the effect in parallel in h ... Full text Link to item Cite

Adenoviral gene transfer to the heart during cardiopulmonary bypass: effect of myocardial protection technique on transgene expression.

Journal Article Eur J Cardiothorac Surg · May 2002 OBJECTIVE: Adenoviral gene transfer to the arrested heart during cardiopulmonary bypass (CPB) is a novel method of allowing prolonged vector contact with the myocardium. In this model we investigated the importance of temperature, duration of arrest and ca ... Full text Link to item Cite

Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure.

Journal Article Mol Pharmacol · April 2002 Cardiovascular regulation is tightly controlled by signaling through G protein-coupled receptors (GPCRs). beta-Adrenergic receptors (ARs) are GPCRs that regulate inotropy and chronotropy in the heart and mediate vasodilation, which critically influences sy ... Full text Link to item Cite

[Gene therapy and benefits in modulating of system beta-adrenergic in cardiac insufficiency].

Journal Article Rev Med Suisse Romande · March 2002 Understanding the basic molecular mechanisms that lead to heart failure may allow to define new targets for myocardial gene therapy. In this way, the alterations of the beta-adrenergic signaling that are typically observed in cardiac insufficiency, may be ... Link to item Cite

Male and female mice overexpressing the beta(2)-adrenergic receptor exhibit differences in ischemia/reperfusion injury: role of nitric oxide.

Journal Article Cardiovascular research · February 2002 ObjectiveCardiac overexpression of beta(2)-adrenergic receptors (beta(2)ARs) in male mice (MTG4) results in increased contractility and increased ischemic injury. Considering recent clinical data indicating that premenopausal women are protected f ... Full text Cite

Seven-transmembrane-spanning receptors and heart function.

Journal Article Nature · January 10, 2002 Understanding precisely how the heart can recognize and respond to many different extracellular signalling molecules, such as neurotransmitters, hormones and growth factors, will aid the identification of new therapeutic targets through which cardiovascula ... Full text Link to item Cite

Expression of a beta-adrenergic receptor kinase inhibitor reverses dysfunction in failing cardiomyocytes.

Journal Article Mol Ther · January 2002 The spontaneously hypertensive heart failure (SHHF) rat shares numerous functional and molecular characteristics of human heart failure (HF), including impairment of beta-adrenergic receptor (AR) signaling with decreased betaAR density and coupling to aden ... Full text Link to item Cite

The putative beta four-adrenergic receptor is a novel state of the beta one-adrenergic receptor

Conference JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY · 2002 Cite

The small EF-hand Ca2+ binding protein S100A1 increases contractility and Ca2+ cycling in rat cardiac myocytes.

Journal Article Basic Res Cardiol · 2002 S100A1 is an interesting Ca2+ binding protein with respect to muscle physiology as it is preferentially expressed in cardiac muscle and colocalizes with the sarcolemmal and the sarcoplasmic reticulum membranes as well as with the sarcomere. It is therefore ... Full text Link to item Cite

Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress.

Journal Article Circulation · January 1, 2002 BACKGROUND: A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortal ... Full text Link to item Cite

Gene-mediated inhibition of the b-adrenergic receptor kinase: a new therapeutic strategy for heart failure.

Journal Article Minerva cardioangiologica · December 2001 Molecular changes that take place during the evolution of heart failure (HF), especially the well characterized beta-adrenergic receptor (betaAR) signaling abnormalities, represent attractive targets for myocardial gene therapy. The beta-adrenergic recepto ... Cite

S100A1: a regulator of myocardial contractility.

Journal Article Proc Natl Acad Sci U S A · November 20, 2001 S100A1, a Ca(2+) binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been found to colocalize with the sarcoplasmic reticulum (SR) and the contractile filaments in cardiac tissue. Because S100A1 is known to modulat ... Full text Link to item Cite

Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery banding.

Journal Article Ann Thorac Surg · November 2001 BACKGROUND: Increased right ventricular (RV) afterload results in RV hypertrophy and dysfunction, as well as increased levels of intracellular beta-adrenergic receptor kinase (betaARK1). We hypothesize that gene transfer of a betaARK1 inhibitor (betaARKct) ... Full text Link to item Cite

Ventricular dysfunction after cardioplegic arrest is improved after myocardial gene transfer of a beta-adrenergic receptor kinase inhibitor.

Journal Article Circulation · October 23, 2001 BACKGROUND: Acute cardiac contractile dysfunction is common after cardiopulmonary bypass (CPB). A potential molecular mechanism is enhanced beta-adrenergic receptor kinase (betaARK1) activity, because beta-adrenergic receptor (betaAR) signaling is altered ... Full text Link to item Cite

Transgenic studies of cardiac adrenergic receptor regulation.

Journal Article J Pharmacol Exp Ther · October 2001 An accumulation of recent data on genetically engineered mouse models suggests that results from studies done in vitro are not necessarily duplicated in vivo. The genetic manipulation of the adrenergic receptor (AR) signaling system in the heart has afford ... Link to item Cite

Genetic manipulation of beta-adrenergic signalling in heart failure.

Journal Article Acta Physiol Scand · September 2001 Heart failure (HF) represents one of the leading causes for hospitalization in developed nations. Despite advances in the management of coronary artery disease, no significant improvements in prognosis have been achieved for HF over the last several decade ... Full text Link to item Cite

Cardiac betaARK1 upregulation induced by chronic salt deprivation in rats.

Journal Article Hypertension · August 2001 The beta-adrenergic receptor (betaAR) kinase (betaARK1) is a G protein-coupled receptor kinase (GRK) that controls cardiac betaAR signaling via receptor phosphorylation, leading to desensitization. We have observed in mice that chronic isoproterenol admini ... Full text Link to item Cite

Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors.

Journal Article J Am Coll Cardiol · August 2001 OBJECTIVES: Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type alpha1B adrenergic receptor (AR) (Tg alpha43), we studied the role of the betaAR kinase (betaARK1) in the evolution of myocardial hypertrophy and its transiti ... Full text Link to item Cite

Cardiac gene delivery with cardiopulmonary bypass.

Journal Article Circulation · July 10, 2001 BACKGROUND: Cardiac gene therapy offers the possibility of enhancing myocardial performance in the compromised heart. However, current gene delivery techniques have limited myocardial transgene expression and pose the risk of extracardiac expression. Isola ... Full text Link to item Cite

Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.

Journal Article Proc Natl Acad Sci U S A · May 8, 2001 Chronic human heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased levels of betaAR kinase 1 (betaARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition ... Full text Open Access Link to item Cite

Myocardial function in hearts with transgenic overexpression of the G protein-coupled receptor kinase 5.

Journal Article Ann Thorac Surg · April 2001 BACKGROUND: Chronic heart failure is associated with impairment of the myocardial beta-adrenergic receptor (beta-AR) system. In this study, the effects of G protein-coupled receptor kinase 5 (GRK5) overexpression on myocardial performance were directly ass ... Full text Link to item Cite

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

Journal Article J Clin Invest · April 2001 The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. ... Full text Open Access Link to item Cite

Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload.

Journal Article Circulation · March 13, 2001 BACKGROUND: Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal-r ... Full text Link to item Cite

In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.

Journal Article Circulation · March 6, 2001 BACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase ( ... Full text Open Access Link to item Cite

Vascular beta-adrenergic receptor system is dysfunctional after myocardial infarction.

Journal Article American journal of physiology. Heart and circulatory physiology · March 2001 We identified abnormalities in the vascular beta-adrenergic receptor (beta-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured beta-AR-mediated hemodynamics, vascular reactivity, and the vasc ... Full text Cite

Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes.

Journal Article Proc Natl Acad Sci U S A · February 13, 2001 The goal of this study was to determine whether beta(1)-adrenergic receptor (AR) and beta(2)-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac beta(2)-AR can a ... Full text Open Access Link to item Cite

Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene.

Journal Article Am J Physiol Heart Circ Physiol · January 2001 A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression of a cardiac alpha-myosin transgene including the R(403)Q mutation and a deletion of a segment of the actin-binding domain. HCM mice show early histopathology and hypertrophy, wit ... Full text Link to item Cite

Cognitive versus behavior therapy in the group treatment of Obsessive-Compulsive disorder.

Journal Article Journal of Consulting and Clinical Psychology · 2001 Full text Cite

Myocardial gene transfer.

Journal Article Curr Cardiol Rep · January 2001 Recent improvements in both gene transfer vectors and in vivo gene delivery techniques have facilitated genetic manipulation of myocardial function and enabled targeted therapy of animal models of cardiac disease and, in particular, heart failure. Increase ... Full text Link to item Cite

Physiological induction of a beta-adrenergic receptor kinase inhibitor transgene preserves ss-adrenergic responsiveness in pressure-overload cardiac hypertrophy.

Journal Article Circulation · November 28, 2000 BACKGROUND: Transgenic mice with constitutive myocardium-targeted expression of a peptide inhibitor of the ss-adrenergic receptor kinase (ssARKct) have increased in vivo cardiac function and enhanced ss-adrenergic receptor (ssAR) responsiveness. METHODS AN ... Full text Link to item Cite

The effect of Gi-protein inactivation on basal, and beta(1)- and beta(2)AR-stimulated contraction of myocytes from transgenic mice overexpressing the beta(2)-adrenoceptor.

Journal Article Br J Pharmacol · October 2000 The atria and ventricles of transgenic mice (TGbeta(2)) with cardiac overexpression of the human beta(2)-adrenoceptor (beta(2)AR) were initially reported to show maximum contractility in the absence of beta-AR stimulation. However, we have previously obser ... Full text Link to item Cite

Vascular beta-adrenergic receptor adenylyl cyclase system in maturation and aging.

Journal Article J Mol Cell Cardiol · September 2000 The objective of this study was to determine how maturation and aging affects beta (beta)-adrenergic receptor (AR) control of arterial vasorelaxation. Left ventricular (LV) hemodynamics and arterial vasorelaxation in thoracic artery segments were studied i ... Full text Link to item Cite

Adenovirus-mediated genetic manipulation of the myocardial beta-adrenergic signaling system in transplanted hearts.

Journal Article J Thorac Cardiovasc Surg · September 2000 OBJECTIVES: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the beta-adrenergic receptor-signaling system, in w ... Full text Link to item Cite

Early effects of right ventricular volume overload on ventricular performance and beta-adrenergic signaling.

Journal Article J Thorac Cardiovasc Surg · August 2000 OBJECTIVE: Right ventricular dysfunction is a poorly understood but persistent clinical problem. This study was undertaken to evaluate ventricular performance and beta-adrenergic receptor signaling in a tricuspid regurgitation model of right ventricular ov ... Full text Link to item Cite

Inhibition of spontaneous beta 2-adrenergic activation rescues beta 1-adrenergic contractile response in cardiomyocytes overexpressing beta 2-adrenoceptor.

Journal Article J Biol Chem · July 14, 2000 Cardiac-specific overexpression of the human beta(2)-adrenergic receptor (AR) in transgenic mice (TG4) enhances basal cardiac function due to ligand-independent spontaneous beta(2)-AR activation. However, agonist-mediated stimulation of either beta(1)-AR o ... Full text Link to item Cite

Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.

Journal Article Proc Natl Acad Sci U S A · May 9, 2000 When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are mediated throu ... Full text Open Access Link to item Cite

Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy.

Journal Article J Biol Chem · February 18, 2000 Activation of phosphoinositide 3-kinases is coupled to both phosphotyrosine/growth factor and G protein-coupled receptors. We explored the role of phosphoinositide 3-kinase activation in myocardium during in vivo pressure overload hypertrophy in mice. Cyto ... Full text Link to item Cite

Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance.

Journal Article Circulation · February 1, 2000 BACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in tran ... Full text Open Access Link to item Cite

Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart.

Journal Article Circ Res · January 7, 2000 G protein-coupled receptor kinases (GRKs) phosphorylate activated G protein-coupled receptors, including alpha(1B)-adrenergic receptors (ARs), resulting in desensitization. In vivo analysis of GRK substrate selectivity has been limited. Therefore, we gener ... Full text Open Access Link to item Cite

Beta-Adrenergic gene therapy for cardiovascular disease.

Journal Article Current controlled trials in cardiovascular medicine · January 2000 Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal h ... Full text Cite

Functional consequences of altering myocardial adrenergic receptor signaling.

Journal Article Annu Rev Physiol · 2000 From the ability to successfully manipulate the mouse genome has come important transgenic and gene-targeted knockout models that impact many areas of biomedical research. Genetically engineered mouse models geared toward the study of cardiovascular regula ... Full text Link to item Cite

Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury.

Journal Article Circ Res · November 26, 1999 Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the ... Full text Open Access Link to item Cite

G beta gamma-mediated signaling: new therapeutic target for proliferative vascular disease.

Journal Article IUBMB Life · September 1999 Proliferation of vascular smooth muscle (VSM) severely affects the outcome of coronary artery bypass and angioplasty procedures, causing the failure of venous grafts or restenosis of the reopened vessel. Investigation into the mechanisms underlying the pro ... Full text Link to item Cite

Potential future therapies for heart failure: gene transfer of beta-adrenergic signaling components.

Journal Article Coron Artery Dis · September 1999 Congestive heart failure (CHF), despite the improved prevention and treatment modalities adopted for cardiovascular disease over the past two decades, remains a significant therapeutic challenge. Efficacious therapies are few, and death rates from CHF cont ... Full text Link to item Cite

In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function.

Journal Article Circulation · August 10, 1999 BACKGROUND: The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac beta-adrenergic receptor (betaAR) system, which is critical in the regulation of myocardial function. Expression of the betaAR kinase (betaARK1), which phosphor ... Full text Open Access Link to item Cite

Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression.

Journal Article J Biol Chem · August 6, 1999 Calsequestrin is a high capacity Ca(2+)-binding protein in the junctional sarcoplasmic reticulum that forms a quaternary complex with junctin, triadin, and the ryanodine receptor. Transgenic mice with cardiac-targeted calsequestrin overexpression show mark ... Full text Link to item Cite

External support modulates G protein expression and receptor coupling in experimental vein grafts.

Journal Article Surgery · August 1999 BACKGROUND: Intimal hyperplasia remains the leading cause of vein graft failure. Various external stenting devices have been shown to reduce the development of intimal hyperplasia in vein grafts. Mitogenic and mechanotransduction signals are known to be me ... Link to item Cite

Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.

Journal Article J Clin Invest · July 1999 Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient an ... Full text Open Access Link to item Cite

Adenovirus-mediated gene transfer of the beta2-adrenergic receptor to donor hearts enhances cardiac function.

Journal Article Gene Ther · July 1999 Gene transfer to modify donor heart function during transplantation has significant therapeutic implications. Recent studies by our laboratory in transgenic mice have shown that overexpression of beta2-adrenergic receptors (beta2-ARs) leads to significantl ... Full text Link to item Cite

Molecular beta-adrenergic signaling abnormalities in failing rabbit hearts after infarction.

Journal Article Am J Physiol · June 1999 We studied alterations in the beta-adrenergic receptor (beta-AR) system of rabbit hearts during the development of heart failure (HF) after myocardial infarction (MI) to determine whether the molecular beta-AR abnormalities associated with human HF exist i ... Full text Link to item Cite

Molecular beta-adrenergic signaling abnormalities in failing rabbit hearts after infarction

Journal Article AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY · June 1, 1999 Link to item Cite

Low- and high-level transgenic expression of beta2-adrenergic receptors differentially affect cardiac hypertrophy and function in Galphaq-overexpressing mice.

Journal Article Proc Natl Acad Sci U S A · May 25, 1999 Transgenic overexpression of Galphaq in the heart triggers events leading to a phenotype of eccentric hypertrophy, depressed ventricular function, marked expression of hypertrophy-associated genes, and depressed beta-adrenergic receptor (betaAR) function. ... Full text Link to item Cite

Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine.

Journal Article Circulation · May 25, 1999 BACKGROUND: Elevated circulating norepinephrine (NE) has been implicated in causing the profound beta-adrenergic receptor (betaAR) downregulation and receptor uncoupling that are characteristic of end-stage human dilated cardiomyopathy, a process mediated ... Full text Link to item Cite

Therapeutic potential of G-protein coupled receptor kinases in the heart.

Journal Article Expert Opin Investig Drugs · May 1999 The actions of G-protein coupled receptor kinases (GRKs) critically regulate beta-adrenergic receptor (betaAR) signalling. In the cardiovascular system, the betaAR signalling pathway controls important responses of the heart such as the ability to contract ... Full text Link to item Cite

L-type calcium current and contractility in ventricular myocytes from mice overexpressing the cardiac beta 2-adrenoceptor.

Journal Article Cardiovascular research · April 1999 ObjectivesThe reported increase in basal activity of hearts from transgenic mice (TG4) overexpressing the human beta 2-adrenoceptor (beta 2-AR) was explained by spontaneously active beta 2-ARs that stimulate the beta-adrenergic cascade in the abse ... Full text Cite

Molecular and functional mechanisms of right ventricular adaptation in chronic pulmonary hypertension.

Journal Article Ann Thorac Surg · April 1999 BACKGROUND: Chronic pulmonary hypertension can lead to compensatory changes in the right ventricle. In this study, the adaptive mechanisms of the right ventricle in the setting of pulmonary hypertension were assessed at the molecular and functional level u ... Full text Link to item Cite

β-drenergic receptor overexpression in the developing mouse heart: Evidence for targeted modulation of ion channels

Journal Article Journal of Physiology · April 1, 1999 1. We studied the effect of overexpression of the β2-adrenergic receptor (β2-AR) in the heart on ion channel currents in single cells isolated from hearts of fetal and neonatal transgenic and wild-type mice. The β2-AR trans ... Full text Cite

Beta2-adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels.

Journal Article J Physiol · April 1, 1999 1. We studied the effect of overexpression of the beta2-adrenergic receptor (beta2-AR) in the heart on ion channel currents in single cells isolated from hearts of fetal and neonatal transgenic and wild-type mice. The beta2-AR transgene construct was under ... Full text Link to item Cite

Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.

Journal Article Proc Natl Acad Sci U S A · March 30, 1999 Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidate ... Full text Open Access Link to item Cite

Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling.

Journal Article J Mol Cell Cardiol · February 1999 In the fetus and neonate, beta-adrenoceptor stimulation fails to produce physiological desensitization. The current study explores the mechanisms underlying the response pattern in neonatal rats. Homologous cardiac beta-adrenergic desensitization caused by ... Full text Link to item Cite

Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes.

Journal Article Circ Res · January 8, 1999 -Transgenic mouse models have been developed to manipulate beta-adrenergic receptor (betaAR) signal transduction. Although several of these models have altered betaAR subtypes, the specific functional sequelae of betaAR stimulation in murine heart, particu ... Full text Open Access Link to item Cite

The myocardial beta-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats.

Conference Hypertension (Dallas, Tex. : 1979) · January 1999 -Responsiveness to beta-adrenergic stimulation is reduced in the failing human myocardium. This results principally from reduced beta-adrenergic receptor (betaAR) density, elevated beta-adrenergic receptor kinase 1 (betaARK1) levels, and functional uncoupl ... Full text Cite

Bbeta-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by beta- but not alpha1-adrenergic stimulation.

Journal Article Hypertension · January 1999 Pressure overload ventricular hypertrophy is accompanied by dysfunctional beta-adrenergic receptor signaling due to increased levels of the beta-adrenergic receptor kinase-1, which phosphorylates and desensitizes beta-adrenergic receptors. In this study, w ... Full text Open Access Link to item Cite

Myocardial G protein-coupled receptor kinases: implications for heart failure therapy.

Journal Article Proc Assoc Am Physicians · 1999 The beta-adrenergic signaling cascade is an important regulator of myocardial function. Significant alterations of this pathway are associated with several cardiovascular diseases, including congestive heart failure (CHF). Included in these alterations is ... Full text Link to item Cite

Exploring the role of the beta-adrenergic receptor kinase in cardiac disease using gene-targeted mice.

Journal Article Trends Cardiovasc Med · 1999 The beta-adrenergic receptor signaling system plays a fundamental role in heart function. Signaling through beta ARs can be dampened by the actions of the beta AR kinase, a kinase whose expression and activity are elevated in chronic human heart failure. I ... Full text Link to item Cite

Myocardial recovery after ischemia and reperfusion injury is significantly impaired in hearts with transgenic overexpression of beta-adrenergic receptor kinase.

Journal Article Circulation · November 10, 1998 BACKGROUND: beta-Adrenergic receptor kinase 1 (beta ARK1) mediates beta-adrenergic receptor signaling via receptor phosphorylation, which results in functional uncoupling. The physiological importance of beta ARK1 on cardiac performance in the setting of i ... Link to item Cite

Myocardial recovery after ischemia and reperfusion injury is significantly impaired in hearts with transgenic overexpression of β- adrenergic receptor kinase

Journal Article Circulation · November 10, 1998 Background - β-Adrenergic receptor kinase 1 (βARK1) mediates β- adrenergic receptor signaling via receptor phosphorylation, which results in functional uncoupling. The physiological importance of βARK1 on cardiac performance in the setting of ischemia and ... Cite

Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade.

Journal Article Circulation · October 27, 1998 BACKGROUND: Impaired myocardial beta-adrenergic receptor (betaAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial ... Full text Open Access Link to item Cite

Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs.

Journal Article Am J Physiol Heart Circ Physiol · October 1, 1998 Transgenic mice were generated with cardiac-specific overexpression of the G protein-coupled receptor kinase 3 (GRK3) to explore the in vivo role of this GRK in cardiac function. GRK3 is expressed in the heart along with the β-adrenergic receptor kinase (β ... Full text Link to item Cite

Cognitive Specificity in Panic and Depression: Implications for Comorbidity

Conference Cognitive Therapy and Research · October 1998 Full text Cite

Adenoviral-mediated inhibition of G beta gamma signaling limits the hyperplastic response in experimental vein grafts.

Journal Article Surgery · August 1998 BACKGROUND: Vein graft intimal hyperplasia is associated with changes in G protein expression. The carboxyl terminus of the beta-adrenergic receptor kinase-1 (beta ARKCT) is known to inhibit G beta gamma-mediated mitogen-activated signaling pathways. This ... Link to item Cite

G protein signaling and vein graft intimal hyperplasia: reduction of intimal hyperplasia in vein grafts by a Gbetagamma inhibitor suggests a major role of G protein signaling in lesion development.

Journal Article Arterioscler Thromb Vasc Biol · August 1998 Vein grafting results in the development of intimal hyperplasia with accompanying changes in guanine nucleotide-binding (G) protein expression and function. Several serum mitogens that act through G protein-coupled receptors, such as lysophosphatidic acid, ... Full text Open Access Link to item Cite

Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice.

Journal Article J Biol Chem · July 17, 1998 We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only hetero ... Full text Link to item Cite

Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.

Journal Article Proc Natl Acad Sci U S A · June 9, 1998 Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is ... Full text Open Access Link to item Cite

Enhanced vasorelaxation by overexpression of beta 2-adrenergic receptors in large arteries.

Journal Article J Mol Cell Cardiol · May 1998 This study was designed to determine if adenoviral-mediated delivery of a transgene encoding the beta 2-adrenergic receptor (beta 2-AR) to the carotid arterial wall could result in alterations in in vivo vascular function. De-endothelialized rat carotid ar ... Full text Link to item Cite

Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy.

Journal Article Science · April 24, 1998 Hormones and neurotransmitters may mediate common responses through receptors that couple to the same class of heterotrimeric guanine nucleotide-binding (G) protein. For example, several receptors that couple to Gq class proteins can induce cardiomyocyte h ... Full text Link to item Cite

Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases.

Journal Article J Clin Invest · March 15, 1998 While an age-associated diminution in myocardial contractile response to beta-adrenergic receptor (beta-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern ... Full text Link to item Cite

Ex vivo adenovirus-mediated gene transfer to the adult rat heart.

Journal Article J Thorac Cardiovasc Surg · March 1998 OBJECTIVE: The ability to transfer genes to adult myocardium may have therapeutic implications for cardiac transplantation. We investigated the feasibility of adenovirus-mediated transfer of marker genes LacZ and Luciferase, as well as the potentially ther ... Full text Link to item Cite

The structure of posttraumatic stress symptoms.

Journal Article Journal of Abnormal Psychology · February 1998 Full text Cite

Myocardial gene transfer of β-adrenergic signaling components as a potential therapy for heart failure

Journal Article Congestive Heart Failure · January 1, 1998 Cardiovascular disease accounts for nearly 40% of all deaths annually in the U.S. Prevention management and advances in medical treatments have dramatically reduced the overall mortality rate due to heart disease. However, death due to chronic HF continues ... Cite

Cardiac hypertrophy is associated with increased β-adrenergic receptor kinase (βARK)

Journal Article FASEB Journal · December 1, 1997 The β-adrenergic receptor (β-AR) is regulated by members of the G protein-coupled receptor kinase (GRK) family. GRK activity is increase in heart failure, however little is known about the role of GRKs in cardiac hypertrophy. Wild type mice were studied af ... Cite

Restoration of beta-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer.

Journal Article Proc Natl Acad Sci U S A · October 28, 1997 Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. ... Full text Open Access Link to item Cite

Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling.

Journal Article J Biol Chem · August 22, 1997 Transgenic mice were generated with cardiac-specific overexpression of the wild-type (WT) alpha1B-adrenergic receptor (AR) using the murine alpha-myosin heavy chain gene promoter. Previously, we described transgenic mice with alpha-myosin heavy chain-direc ... Full text Link to item Cite

Mechanism of beta-adrenergic receptor desensitization in cardiac hypertrophy is increased beta-adrenergic receptor kinase.

Journal Article J Biol Chem · July 4, 1997 Pressure overload cardiac hypertrophy in the mouse was achieved following 7 days of transverse aortic constriction. This was associated with marked beta-adrenergic receptor (beta-AR) desensitization in vivo, as determined by a blunted inotropic response to ... Full text Link to item Cite

Gene transfer strategies for augmenting cardiac function.

Journal Article Trends Cardiovasc Med · July 1997 Recent transgenic as well as gene-targeted animal models have greatly increased our understanding of the molecular mechanisms of normal and compromised heart function. These studies have raised the possibility of using somatic gene transfer as a means for ... Full text Link to item Cite

Sensitivity of Outcome Measures for Treatments of Generalized Social Phobia

Journal Article Assessment · June 1997 To accurately evaluate treatments of generalized social phobia, it is not sufficient that measures be reliable and valid, they also must be sensitive to treatment-related changes. The present study evaluated the sensitivity of the following five m ... Full text Cite

In vivo pulmonary artery adenoviral gene transfer of nitric oxide synthase enhances pulmonary nitric oxide production

Journal Article Heart · May 1, 1997 Nitric oxide (NO), generated by nitric oxide synthase (NOS), has key regulatory roles in the normal pulmonary circulation, and also inhibits pathological processes such as platelet aggregation, neutrophil adhesion and smooth muscle cell proliferation. NO p ... Cite

Potentiation of beta-adrenergic signaling by gene transfer.

Journal Article Proc Assoc Am Physicians · May 1997 The beta-adrenergic signaling cascade is an important regulator of myocardial function. Numerous abnormalities occur in this pathway and are associated with impaired cardiac contractility in patients with congestive heart failure (CHF). These signaling def ... Link to item Cite

Cardiac function in genetically engineered mice with altered adrenergic receptor signaling.

Journal Article Am J Physiol · April 1997 In disease states such as heart failure, catecholamines released from sympathetic nerve endings and the adrenal medulla play a central role in the adaptive and maladaptive physiological response to altered tissue perfusion. G protein-coupled receptors are ... Full text Link to item Cite

Cardiac function in genetically engineered mice with altered adrenergic receptor signaling

Journal Article AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY · April 1, 1997 Link to item Cite

Antisense oligonucleotide to proto-oncogene c-myb inhibits the formation of intimal hyperplasia in experimental vein grafts.

Journal Article J Vasc Surg · March 1997 BACKGROUND: The development of intimal hyperplasia is a major cause of early vein graft failure. The study examines the effects of locally delivered antisense oligonucleotides to the proto-oncogene c-myb on the development of vein graft intimal hyperplasia ... Full text Link to item Cite

Reliability and Validity of the Cognition Checklist With Psychiatric Outpatients

Journal Article Assessment · March 1997 The Cognition Checklist Anxiety scale (CCL-A) and Depression scale (CCL-D) were administered to psychiatric outpatients with panic disorder ( n = 51), major depression ( n = 44), or panic disorder and major depression ( n = 38). Both scales showed ... Full text Cite

Transgenic manipulation of β-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine

Journal Article American Journal of Physiology - Heart and Circulatory Physiology · February 20, 1997 To determine the direct functional significance of the β-adrenergic receptor (AR) kinase 1 (βARK1) on myocardial performance in the absence of tonic sympathoadrenal neural activation and mechanical loading, we measured the contractile responses to acute β1 ... Cite

Potentiation of beta-adrenergic signaling by adenoviral-mediated gene transfer in adult rabbit ventricular myocytes.

Journal Article J Clin Invest · January 15, 1997 Our laboratory has been testing the hypothesis that genetic modulation of the beta-adrenergic signaling cascade can enhance cardiac function. We have previously shown that transgenic mice with cardiac overexpression of either the human beta2-adrenergic rec ... Full text Open Access Link to item Cite

Gene therapy for chronic heart failure

Journal Article ACC Current Journal Review · January 1, 1997 Full text Cite

G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors.

Journal Article Adv Second Messenger Phosphoprotein Res · 1997 G-protein-coupled receptors that mediate cellular responses to a variety of humoral, endothelial-, or platelet-derived substances are able to stimulate MAP kinase activity. In transfected model systems, G-protein-coupled receptors that couple to pertussis ... Link to item Cite

Transgenic manipulation of beta-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine.

Journal Article Am J Physiol · January 1997 To determine the direct functional significance of the beta-adrenergic receptor (AR) kinase 1 (beta ARK1) on myocardial performance in the absence of tonic sympathoadrenal neural activation and mechanical loading, we measured the contractile responses to a ... Full text Link to item Cite

Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency.

Journal Article J Clin Invest · December 1, 1996 To circumvent the embryonic lethality of a complete deficiency in insulin-like growth factor 1 (IGF-1), we generated mice homozygous for a site-specific insertional event that created a mutant IGF-1 allele (igf1m). These mice have IGF-1 levels 30% of wild ... Full text Link to item Cite

Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function.

Journal Article Proc Natl Acad Sci U S A · November 12, 1996 The beta-adrenergic receptor kinase 1 (beta ARK1) is a member of the G protein-coupled receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled receptors. We have cloned and disrupted the bet ... Full text Open Access Link to item Cite

Phosphatidylinositol 4,5-bisphosphate (PIP2)-enhanced G protein-coupled receptor kinase (GRK) activity. Location, structure, and regulation of the PIP2 binding site distinguishes the GRK subfamilies.

Journal Article J Biol Chem · October 4, 1996 The G protein-coupled receptor kinases (GRKs) phosphorylate agonist occupied G protein-coupled receptors and play an important role in mediating receptor desensitization. The localization of these enzymes to their membrane incorporated substrates is requir ... Full text Link to item Cite

Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice.

Journal Article Proc Natl Acad Sci U S A · September 3, 1996 Transgenic mice were generated with cardiac-specific overexpression of the G protein-coupled receptor kinase-5 (GRK5), a serine/threonine kinase most abundantly expressed in the heart compared with other tissues. Animals overexpressing GRK5 showed marked b ... Full text Open Access Link to item Cite

Myocardial beta-adrenergic receptor signaling in vivo: insights from transgenic mice.

Journal Article J Mol Med (Berl) · September 1996 Heart failure is a problem of increasing importance in cardiovascular medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor ... Full text Link to item Cite

G(o)-protein alpha-subunits activate mitogen-activated protein kinase via a novel protein kinase C-dependent mechanism.

Journal Article J Biol Chem · January 19, 1996 Mitogen-activated protein kinase (MAPK) is activated in response to both receptor tyrosine kinases and G-protein-coupled receptors. Recently, Gi-coupled receptors, such as the alpha 2A adrenergic receptor, were shown to mediate Ras-dependent MAPK activatio ... Full text Link to item Cite

Assessment and treatment of motor vehicle accident victims

Journal Article Cognitive and Behavioral Practice · December 1995 Full text Cite

Role of phosphorylation in agonist-promoted beta 2-adrenergic receptor sequestration. Rescue of a sequestration-defective mutant receptor by beta ARK1.

Journal Article J Biol Chem · October 20, 1995 The beta 2-adrenergic receptor (beta 2AR) belongs to the large family of G protein-coupled receptors. Mutation of tyrosine residue 326 to an alanine resulted in a beta 2AR mutant (beta 2AR-Y326A) that was defective in its ability to sequester and was less ... Full text Link to item Cite

Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation.

Journal Article J Biol Chem · July 21, 1995 Receptors that couple to the heterotrimeric G proteins, Gi or Gq, can stimulate phosphoinositide (PI) hydrolysis and mitogen-activated protein kinase (MAPK) activation. PI hydrolysis produces inositol 1,4,5-trisphosphate and diacylglycerol, leading to acti ... Full text Link to item Cite

Mutational analysis of the pleckstrin homology domain of the beta-adrenergic receptor kinase. Differential effects on G beta gamma and phosphatidylinositol 4,5-bisphosphate binding.

Journal Article J Biol Chem · July 14, 1995 The beta gamma subunits of heterotrimeric G proteins (G beta gamma) play a variety of roles in cellular signaling, one of which is membrane targeting of the beta-adrenergic receptor kinase (beta ARK). This is accomplished via a physical interaction of G be ... Full text Link to item Cite

G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor.

Journal Article J Biol Chem · July 14, 1995 The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth factor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine protein kinase activity. In Rat 1 fibroblasts, stim ... Full text Link to item Cite

Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor.

Journal Article Science · June 2, 1995 Transgenic mice were created with cardiac-specific overexpression of the beta-adrenergic receptor kinase-1 (beta ARK1) or a beta ARK inhibitor. Animals overexpressing beta ARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contracti ... Full text Link to item Cite

Effect of cellular expression of pleckstrin homology domains on Gi-coupled receptor signaling.

Journal Article J Biol Chem · June 2, 1995 Pleckstrin homology (PH) domains are 90-110 amino acid regions of protein sequence homology that are found in a variety of proteins involved in signal transduction and growth control. We have previously reported that the PH domains of several proteins, inc ... Full text Link to item Cite

Cardiac muscarinic potassium channel activity is attenuated by inhibitors of G beta gamma.

Journal Article Circ Res · May 1995 The cardiac muscarinic potassium channel (IK.ACh) is activated by a G protein upon receptor stimulation with acetylcholine. The G protein subunit responsible for activation (G alpha versus G beta gamma) has been disputed. We used G beta gamma inhibitors de ... Full text Link to item Cite

G beta gamma interactions with PH domains and Ras-MAPK signaling pathways.

Journal Article Trends Biochem Sci · April 1995 G-protein-coupled receptor signaling and receptor tyrosine kinase (RTK) signaling are two mechanisms of transmembrane communication used by numerous extracellular agents and stimuli. The beta gamma-subunit complex of G proteins mediates many of the functio ... Full text Link to item Cite

Anxiety disorders due to motor vehicle accidents: Nature and treatment

Journal Article Clinical Psychology Review · January 1995 Full text Cite

Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras.

Journal Article Proc Natl Acad Sci U S A · December 20, 1994 Stimulation of Gi-coupled receptors leads to the activation of mitogen-activated protein kinases (MAP kinases). In several cell types, this appears to be dependent on the activation of p21ras (Ras). Which G-protein subunit(s) (G alpha or the G beta gamma c ... Full text Open Access Link to item Cite

Functionally active targeting domain of the beta-adrenergic receptor kinase: an inhibitor of G beta gamma-mediated stimulation of type II adenylyl cyclase.

Journal Article Proc Natl Acad Sci U S A · April 26, 1994 The beta-adrenergic receptor kinase (beta ARK) phosphorylates its membrane-associated receptor substrates, such as the beta-adrenergic receptor, triggering events leading to receptor desensitization. beta ARK activity is markedly stimulated by the isopreny ... Full text Open Access Link to item Cite

Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases.

Journal Article J Biol Chem · March 4, 1994 A novel member of the family of G protein-coupled receptor kinases (GRKs), named GRK5, has been cloned from bovine taste epithelium. The cDNA sequence predicts a 590-amino acid protein with high overall similarity to rhodopsin kinase. GRK5 mRNA is found mo ... Link to item Cite

Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G beta gamma-mediated signaling.

Journal Article J Biol Chem · February 25, 1994 The beta gamma subunits (G beta gamma) of heterotrimeric G proteins modulate the activity of several signal-transducing effector molecules including G protein-coupled receptor kinases. G beta gamma binds to the carboxyl terminus of the beta-adrenergic rece ... Link to item Cite

Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase. Functional specificity among G-protein coupled receptor kinases.

Journal Article J Biol Chem · January 14, 1994 The thrombin receptor, a member of the seven membrane-spanning superfamily of G-protein coupled receptors, is activated by an irreversible proteolytic mechanism, but signaling by activated thrombin receptors shuts off soon after receptor activation. This s ... Link to item Cite

Olfactory desensitization requires membrane targeting of receptor kinase mediated by beta gamma-subunits of heterotrimeric G proteins.

Journal Article J Biol Chem · January 7, 1994 Olfaction is mediated by G protein-coupled receptors. In isolated rat olfactory cilia, odorants such as citralva stimulate a burst of cAMP, which peaks in 50 ms and returns almost to base-line level within 150 ms in the continuing presence of odorant. This ... Link to item Cite

ISOPRENYLATION IN THE REGULATION OF SENSORY RECEPTORS

Journal Article JOURNAL OF NEUROCHEMISTRY · January 1, 1994 Link to item Cite

The binding site for the beta gamma subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase.

Journal Article J Biol Chem · April 15, 1993 The beta gamma subunits of heterotrimeric G proteins play important roles in regulating receptor-stimulated signal transduction processes. Recently appreciated among these is their role in the signaling events that lead to the phosphorylation and subsequen ... Link to item Cite

Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases.

Journal Article Nature · September 10, 1992 Rhodopsin kinase and beta-adrenergic receptor kinase (beta ARK) are related members of a serine/threonine kinase family that specifically initiate deactivation of G-protein-coupled receptors. After stimulus-mediated receptor activation, these cytoplasmic k ... Full text Link to item Cite

How does anxiety sensitivity vary across the anxiety disorders?

Journal Article Journal of Anxiety Disorders · July 1992 Full text Cite

Mutually exclusive exon splicing of the cardiac calcium channel alpha 1 subunit gene generates developmentally regulated isoforms in the rat heart.

Journal Article Proc Natl Acad Sci U S A · February 15, 1992 Several clones were isolated from a rat genomic library in order to further characterize a region of variability within the third membrane-spanning region of the fourth motif (IVS3) of the L-type voltage-dependent calcium channel. We report here that this ... Full text Link to item Cite

Native-type DHP-sensitive calcium channel currents are produced by cloned rat aortic smooth muscle and cardiac alpha 1 subunits expressed in Xenopus laevis oocytes and are regulated by alpha 2- and beta-subunits.

Journal Article FEBS Lett · February 10, 1992 Native tissue-like L-type voltage-dependent calcium channels (L-VDCC's) were expressed by in vitro transcribed cRNA injection of rat aorta or rabbit cardiac alpha 1 subunit into Xenopus laevis oocytes. Co-injection of VSM-alpha 1 with the cloned skeletal m ... Full text Link to item Cite

Calcium channels from Cyprinus carpio skeletal muscle.

Journal Article Proc Natl Acad Sci U S A · February 1, 1991 The complete amino acid sequence of the L-type calcium channel alpha 1 subunit from the carp (Cyprinus carpio) white skeletal muscle was deduced by cDNA cloning and sequence analysis. The open reading frame encodes 1852 amino acids (Mr 210,060). A 155-amin ... Full text Link to item Cite

Anxiety sensitivity, trait anxiety, and the anxiety disorders

Journal Article Journal of Anxiety Disorders · January 1991 Full text Cite

cDNA cloning of a dihydropyridine-sensitive calcium channel from rat aorta. Evidence for the existence of alternatively spliced forms.

Journal Article J Biol Chem · October 15, 1990 Several complementary DNAs have been isolated from rat aorta cDNA libraries that encode the alpha 1 subunit of the L-type dihydropyridine-sensitive voltage-dependent calcium channel (VDCC). The clones were isolated using previously cloned rabbit skeletal a ... Link to item Cite

Toward an understanding of the dihydropyridine-sensitive calcium channel.

Journal Article Biochem Pharmacol · April 1, 1990 The dihydropyridine-sensitive calcium channel continues to fascinate scientific investigators. Each new discovery leads to more complexity. Further work elucidating the molecular structures and functions of the various isoforms of the channel will lead us ... Full text Link to item Cite

Characterization of cDNA clones encoding two putative isoforms of the alpha 1 subunit of the dihydropyridine-sensitive voltage-dependent calcium channel isolated from rat brain and rat aorta.

Journal Article FEBS Lett · July 3, 1989 cDNA clones encoding rat brain and rat aorta isoforms of the alpha 1 subunit of the dihydropyridine-sensitive, voltage-dependent calcium channel were isolated and sequenced. These tissue-specific cDNA clones share significant amino acid similarity with the ... Full text Link to item Cite

Sequence and expression of mRNAs encoding the alpha 1 and alpha 2 subunits of a DHP-sensitive calcium channel.

Journal Article Science · September 23, 1988 Complementary DNAs were isolated and used to deduce the primary structures of the alpha 1 and alpha 2 subunits of the dihydropyridine-sensitive, voltage-dependent calcium channel from rabbit skeletal muscle. The alpha 1 subunit, which contains putative bin ... Full text Link to item Cite

A possible role for the endothelium in porcine coronary smooth muscle responses to dihydropyridine calcium channel modulators.

Journal Article J Pharmacol Exp Ther · May 1987 The role of the endothelium in contraction and relaxation produced by the dihydropyridine calcium channel modulators was examined in porcine coronary smooth muscle. The optically pure dihydropyridine calcium agonists (+)-S202-791 and (-)-Bay k 8644 both pr ... Link to item Cite