Scholars@Duke
Howard Allan Rockman

Howard Allan Rockman

Edward S. Orgain Distinguished Professor of Cardiology, in the School of Medicine
Medicine, Cardiology
h.rockman@duke.edu
Duke Box 102151, Durham, NC 27710
226 Clin Res Lab Bldg, Duke Box 102151, Durham, NC 27710

Selected Publications

Antibodies expand the scope of angiotensin receptor pharmacology.

Journal Article Nat Chem Biol · December 2024 G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often l ... Full text Link to item Cite

USP20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.

Journal Article Am J Physiol Heart Circ Physiol · November 1, 2024 Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well characterized. To def ... Full text Link to item Cite

Engineering and Characterization of a Long-Half-Life Relaxin Receptor RXFP1 Agonist.

Journal Article Mol Pharm · September 2, 2024 Relaxin-2 is a peptide hormone with important roles in human cardiovascular and reproductive biology. Its ability to activate cellular responses such as vasodilation, angiogenesis, and anti-inflammatory and antifibrotic effects has led to significant inter ... Full text Link to item Cite

Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways.

Journal Article Sci Signal · August 13, 2024 Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or β-arrestin. These different active conformations are thought to engage distinct ... Full text Link to item Cite

G Protein-Coupled Receptors: A Century of Research and Discovery.

Journal Article Circ Res · June 21, 2024 GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug ... Full text Link to item Cite

G protein-coupled receptors: from radioligand binding to cellular signaling.

Journal Article J Clin Invest · March 1, 2024 Radioligand binding techniques facilitated the identification and study of G-protein coupled receptors that now represent the largest class of targets for therapeutic drugs. ... Full text Link to item Cite

How carvedilol does not activate β2-adrenoceptors.

Journal Article Nat Commun · November 30, 2023 Full text Link to item Cite

Pathophysiology and pharmacology of G protein-coupled receptors in the heart.

Journal Article Cardiovasc Res · May 22, 2023 G protein-coupled receptors (GPCRs), comprising the largest superfamily of cell surface receptors, serve as fundamental modulators of cardiac health and disease owing to their key roles in the regulation of heart rate, contractile dynamics, and cardiac fun ... Full text Link to item Cite

G protein-coupled receptor signaling: transducers and effectors.

Journal Article Am J Physiol Cell Physiol · September 1, 2022 G protein-coupled receptors (GPCRs) are of considerable interest due to their importance in a wide range of physiological functions and in a large number of Food and Drug Administration (FDA)-approved drugs as therapeutic entities. With continued study of ... Full text Link to item Cite

Late onset cardiovascular dysfunction in adult mice resulting from galactic cosmic ray exposure.

Journal Article iScience · April 15, 2022 The complex and inaccessible space radiation environment poses an unresolved risk to astronaut cardiovascular health during long-term space exploration missions. To model this risk, healthy male c57BL/6 mice aged six months (corresponding to an astronaut o ... Full text Link to item Cite

Proximity labeling for investigating protein-protein interactions.

Chapter · 2022 The study of protein complexes and protein-protein interactions is of great importance due to their fundamental roles in cellular function. Proximity labeling, often coupled with mass spectrometry, has become a powerful and versatile tool for studying prot ... Full text Link to item Cite

β-Arrestin-Biased Allosteric Modulator Potentiates Carvedilol-Stimulated β Adrenergic Receptor Cardioprotection.

Journal Article Mol Pharmacol · December 2021 β 1 adrenergic receptors (β 1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, β 1ARs activate cellular signaling by primarily coupling to Gs proteins to activate ad ... Full text Link to item Cite

Mapping Angiotensin II Type 1 Receptor-Biased Signaling Using Proximity Labeling and Proteomics Identifies Diverse Actions of Biased Agonists.

Journal Article J Proteome Res · June 4, 2021 Angiotensin II type 1 receptors (AT1Rs) are one of the most widely studied G-protein-coupled receptors. To fully appreciate the diversity in cellular signaling profiles activated by AT1R transducer-biased ligands, we utilized peroxidase-catalyzed proximity ... Full text Open Access Link to item Cite

Synthetic nanobodies as angiotensin receptor blockers.

Journal Article Proc Natl Acad Sci U S A · August 18, 2020 There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine ... Full text Link to item Cite

Abstract MP133: Development of β-arrestin-biased Positive Allosteric Modulators for the β 1 Adrenergic Receptor

Conference Circulation Research · July 31, 2020 The β 1 adrenergic receptor (β 1 AR) is a central regulator of cardiac function and an important therapeutic target for cardiac diseases. Two eme ... Full text Cite

The β-arrestin-biased β-adrenergic receptor blocker carvedilol enhances skeletal muscle contractility.

Journal Article Proc Natl Acad Sci U S A · June 2, 2020 A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and incr ... Full text Open Access Link to item Cite

A murine model of increased coronary sinus pressure induces myocardial edema with cardiac lymphatic dilation and fibrosis.

Journal Article Am J Physiol Heart Circ Physiol · April 1, 2020 Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and hypertension. The aim of this study was to establish a murine model of myocardial edema and elucidate the response of cardiac l ... Full text Link to item Cite

Come sail away.

Journal Article JCI Insight · August 8, 2019 Full text Link to item Cite

The deubiquitinase ubiquitin-specific protease 20 is a positive modulator of myocardial β1-adrenergic receptor expression and signaling.

Journal Article J Biol Chem · February 15, 2019 Reversible ubiquitination of G protein-coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial β1-adrenergic receptors (β1ARs) is unknown. We report that ubiquitin-specific protease 20 (USP20) deubiquitinate ... Full text Link to item Cite

β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility.

Journal Article Skelet Muscle · December 27, 2018 BACKGROUND: β2-adrenergic receptors (β2ARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of β2AR stimulation on skeletal muscle is anabolic growth, which has l ... Full text Open Access Link to item Cite

The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction.

Journal Article J Clin Invest · November 1, 2018 Cardiac two-pore domain potassium channels (K2P) exist in organisms from Drosophila to humans; however, their role in cardiac function is not known. We identified a K2P gene, CG8713 (sandman), in a Drosophila genetic screen and show that sandman is critica ... Full text Link to item Cite

Manifold roles of β-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9.

Journal Article Sci Signal · September 25, 2018 G protein-coupled receptors (GPCRs) use diverse mechanisms to regulate the mitogen-activated protein kinases ERK1/2. β-Arrestins (βArr1/2) are ubiquitous inhibitors of G protein signaling, promoting GPCR desensitization and internalization and serving as s ... Full text Link to item Cite

G-Protein-Coupled Receptors in Heart Disease.

Journal Article Circ Res · August 31, 2018 GPCRs (G-protein [guanine nucleotide-binding protein]-coupled receptors) play a central physiological role in the regulation of cardiac function in both health and disease and thus represent one of the largest class of surface receptors targeted by drugs. ... Full text Link to item Cite

Mechanoactivation of the angiotensin II type 1 receptor induces β-arrestin-biased signaling through Gαi coupling.

Journal Article J Cell Biochem · April 2018 Ligand activation of the angiotensin II type 1 receptor (AT1R), a member of the G protein-coupled receptor (GPCR) family, stimulates intracellular signaling to mediate a variety of physiological responses. The AT1R is also known to be a mechanical sensor. ... Full text Link to item Cite

We're listening.

Journal Article JCI Insight · January 25, 2018 Full text Link to item Cite

Gαi is required for carvedilol-induced β1 adrenergic receptor β-arrestin biased signaling.

Journal Article Nat Commun · November 22, 2017 The β1 adrenergic receptor (β1AR) is recognized as a classical Gαs-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein β-arrestin. Some βAR ligands, such as carved ... 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

לְדוֹר וָדוֹר.

Journal Article J Clin Invest · June 1, 2017 L'dor vador, transliterated from the Hebrew above, is an ancient concept in Judaic scripture meaning "from generation to generation," which is now generally interpreted to mean that we have a responsibility to pass on teachings to future generations. It ha ... Full text Link to item Cite

A successful launch.

Journal Article JCI Insight · January 26, 2017 Full text Link to item Cite

β-Arrestin mediates the Frank-Starling mechanism of cardiac contractility.

Journal Article Proc Natl Acad Sci U S A · December 13, 2016 The Frank-Starling law of the heart is a physiological phenomenon that describes an intrinsic property of heart muscle in which increased cardiac filling leads to enhanced cardiac contractility. Identified more than a century ago, the Frank-Starling relati ... Full text Link to item Cite

Phosphorylation of Src by phosphoinositide 3-kinase regulates beta-adrenergic receptor-mediated EGFR transactivation.

Journal Article Cell Signal · October 2016 β2-Adrenergic receptors (β2AR) transactivate epidermal growth factor receptors (EGFR) through formation of a β2AR-EGFR complex that requires activation of Src to mediate signaling. Here, we show that both lipid and protein kinase activities of the bifuncti ... Full text Link to item Cite

G Protein-coupled Receptor Biased Agonism.

Journal Article J Cardiovasc Pharmacol · March 2016 G protein-coupled receptors are the largest family of targets for current therapeutics. The classic model of their activation was binary, where agonist binding induced an active conformation and subsequent downstream signaling. Subsequently, the revised co ... Full text Link to item Cite

New kid on the block.

Journal Article J Clin Invest · January 4, 2016 As Editor of the Journal of Clinical Investigation, I am pleased to announce the January 2016 launch of JCI Insight, which will publish well-executed, high-quality research across biomedicine that presents a focused yet insightful line of investigation. Th ... Full text Link to item Cite

Pacemaker-induced transient asynchrony suppresses heart failure progression.

Journal Article Sci Transl Med · December 23, 2015 Uncoordinated contraction from electromechanical delay worsens heart failure pathophysiology and prognosis, but restoring coordination with biventricular pacing, known as cardiac resynchronization therapy (CRT), improves both. However, not every patient qu ... Full text Link to item Cite

The role of β-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome.

Journal Article Am J Physiol Heart Circ Physiol · November 2015 Ang II type 1a receptor (AT1aR)-mediated activation of MAPKs contributes to thoracic aortic aneurysm (TAA) development in Marfan syndrome (MFS). β-Arrestin2 (βarr2) is known to mediate AT1aR-dependent MAPK activation, as well as proproliferative and profib ... Full text Link to item Cite

Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart.

Journal Article Cell Rep · October 20, 2015 Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and us ... Full text Link to item Cite

Circulating Exosomes Induced by Cardiac Pressure Overload Contain Functional Angiotensin II Type 1 Receptors.

Journal Article Circulation · June 16, 2015 BACKGROUND: Whether biomechanical force on the heart can induce exosome secretion to modulate cardiovascular function is not known. We investigated the secretion and activity of exosomes containing a key receptor in cardiovascular function, the angiotensin ... Full text Link to item Cite

Allosteric modulation of β-arrestin-biased angiotensin II type 1 receptor signaling by membrane stretch.

Journal Article J Biol Chem · October 10, 2014 It has recently been appreciated that the angiotensin II type 1 receptor (AT1R), a prototypic member of the G protein-coupled receptor superfamily, also functions as a mechanosensor. Specifically, mechanical stretch activates the AT1R to promote downstream ... Full text Link to item Cite

Galactokinase is a novel modifier of calcineurin-induced cardiomyopathy in Drosophila.

Journal Article Genetics · October 2014 Activated/uninhibited calcineurin is both necessary and sufficient to induce cardiac hypertrophy, a condition that often leads to dilated cardiomyopathy, heart failure, and sudden cardiac death. We expressed constitutively active calcineurin in the adult h ... Full text Link to item Cite

Happy birthday JCI.

Journal Article J Clin Invest · October 2014 On the occasion of the ninetieth anniversary of the JCI, I am again humbled by the remarkable insight and passion of our pioneering founders when they created the Journal of Clinical Investigation in 1924. ... 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

Normal cardiac function in mice with supraphysiological cardiac creatine levels.

Journal Article Am J Physiol Heart Circ Physiol · February 2014 Creatine and phosphocreatine levels are decreased in heart failure, and reductions in myocellular phosphocreatine levels predict the severity of the disease and portend adverse outcomes. Previous studies of transgenic mouse models with increased creatine c ... Full text Link to item Cite

Waste not, want not.

Journal Article J Clin Invest · February 2014 As of the writing of this Editorial, the current JCI Editorial Board has evaluated approximately 7,000 manuscripts over the past 22 months for their suitability for publication in our journal. While many of you have received a negative decision on your man ... Full text Link to item Cite

Anatomical and functional imaging of myocardial infarction in mice using micro-CT and eXIA 160 contrast agent.

Journal Article Contrast Media Mol Imaging · 2014 Noninvasive small animal imaging techniques are essential for evaluation of cardiac disease and potential therapeutics. A novel preclinical iodinated contrast agent called eXIA 160 has recently been developed, which has been evaluated for micro-CT cardiac ... Full text Link to item Cite

Tempus fugit.

Journal Article J Clin Invest · March 1, 2013 As I draft this editorial, it is almost a year into our stewardship as editors of the JCI. Previous Journal Editors have told me that the evaluation of manuscripts submitted across a broad range of topics and specialties was a highlight for their time as J ... Full text Link to item Cite

Modulating G protein-coupled receptors to effect reverse cardiac remodeling

Chapter · January 1, 2013 G protein-coupled receptors (GPCRs) represent the largest known family of transmembrane receptors and therapeutic targets in cardiovascular medicine, accounting for a large number of marketed cardiovascular pharmaceuticals. Traditionally, GPCR stimulation ... Full text Cite

Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction.

Journal Article J Mol Cell Cardiol · January 2013 Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase whose biological function remains largely unknown. We have recently shown that TNNI3K expression greatly accelerates cardiac dysfunction in mouse models of cardiomyopathy, indicati ... Full text Link to item Cite

Clinical medicine

Journal Article Journal of Clinical Investigation · December 3, 2012 With the December issue of the Journal of Clinical Investigation, I announce the launch of a new category of manuscript called "Clinical Medicine,"along with new editorial board members to adjudicate the peer-review process. With this initiative, the journ ... Full text Cite

β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury.

Journal Article Am J Physiol Heart Circ Physiol · October 15, 2012 Pharmacological blockade of the ANG II type 1 receptor (AT1R) is a common therapy for treatment of congestive heart failure and hypertension. Increasing evidence suggests that selective engagement of β-arrestin-mediated AT1R signaling, referred to as biase ... Full text Link to item Cite

p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.

Journal Article Sci Signal · July 24, 2012 Radiation therapy, which is used for the treatment of some cancers, can cause delayed heart damage. In the heart, p53 influences myocardial injury that occurs after multiple types of stress. Here, we demonstrated that p53 functioned in endothelial cells to ... Full text Link to item Cite

Great expectations.

Journal Article J Clin Invest · April 2012 On the occasion of the 200th anniversary of Charles Dickens's birth, I am struck by his creative genius and by the parallel between the intellectual development of his protagonists and the evolution of peer review. Like many of his novels and serial writin ... Full text Link to item Cite

Deletion of Siah-interacting protein gene in Drosophila causes cardiomyopathy.

Journal Article Mol Genet Genomics · April 2012 Drosophila is a useful model organism in which the genetics of human diseases, including recent advances in identification of the genetics of heart development and disease in the fly, can be studied. To identify novel genes that cause cardiomyopathy, we pe ... Full text Link to item Cite

Tradition, tradition.

Journal Article J Clin Invest · March 2012 Starting with this issue, the Editorial duties for the JCI move to Duke University and the University of North Carolina at Chapel Hill. As we begin our five-year tenure at the helm of this prestigious journal, the tradition of excellence that these two sch ... Full text Link to item Cite

Editorial position on publishing articles on human organ transplantation.

Journal Article J Clin Invest · January 2012 The practice of transplanting organs from executed prisoners in China appears to be widespread. We vigorously condemn this practice and, effective immediately, will not consider manuscripts on human organ transplantation for publication unless appropriate ... Full text Link to item Cite

Cardiomyopathy is associated with ribosomal protein gene haplo-insufficiency in Drosophila melanogaster.

Journal Article Genetics · November 2011 The Minute syndrome in Drosophila melanogaster is characterized by delayed development, poor fertility, and short slender bristles. Many Minute loci correspond to disruptions of genes for cytoplasmic ribosomal proteins, and therefore the phenotype has been ... Full text Link to item Cite

Β-arrestin: a signaling molecule and potential therapeutic target for heart failure.

Journal Article J Mol Cell Cardiol · October 2011 Currently, some of the most effective treatments for heart failure target GPCRs such as the beta-adrenergic receptors (β1AR and β2AR) and angiotensin II type IA receptors (AT1aR). Ligands for these receptors not only function by blocking the deleterious G- ... Full text Link to item Cite

Drosophila, genetic screens, and cardiac function.

Journal Article Circ Res · September 16, 2011 The fruit fly, Drosophila melanogaster, has been used to study genetics, development, and signaling for nearly a century, but only over the past few decades has this tremendous resource been the focus of cardiovascular research. Fly genetics offers sophist ... Full text Link to item Cite

A method to measure myocardial calcium handling in adult Drosophila.

Journal Article Circ Res · May 27, 2011 RATIONALE: Normal cardiac physiology requires highly regulated cytosolic Ca(2+) concentrations and abnormalities in Ca(2+) handling are associated with heart failure. The majority of approaches to identifying the components that regulate intracellular Ca(2 ... Full text Link to item Cite

β-Arrestin mediates oxytocin receptor signaling, which regulates uterine contractility and cellular migration.

Journal Article Am J Physiol Endocrinol Metab · March 2011 Desensitization of the oxytocin receptor (OXTR) in the setting of prolonged oxytocin exposure may lead to dysfunctional labor, which increases the risk for cesarean delivery, and uterine atony, which may result in postpartum hemorrhage. The molecular mecha ... Full text Link to item Cite

Functional selectivity in adrenergic and angiotensin signaling systems.

Journal Article Mol Pharmacol · December 2010 β-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as antagonists for these receptors have positively affected the morbidity and mortality of pat ... Full text Link to item Cite

Troglitazone stimulates beta-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor.

Journal Article Biochem Biophys Res Commun · June 11, 2010 Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPAR gamma-independent signaling events. Selec ... Full text Link to item Cite

beta-Arrestin-biased agonism of the angiotensin receptor induced by mechanical stress.

Journal Article Sci Signal · June 8, 2010 beta-Arrestins, which were originally characterized as terminators of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) signaling, also act as important signal transducers. An emerging concept in GPCR signaling is beta-a ... Full text Link to item Cite

Science signaling podcast: 8 June 2010

Journal Article Science Signaling · June 8, 2010 Full text Cite

Cardiac copper deficiency activates a systemic signaling mechanism that communicates with the copper acquisition and storage organs.

Journal Article Cell Metab · May 5, 2010 Copper (Cu) is an essential cofactor for a variety of metabolic functions, and the regulation of systemic Cu metabolism is critical to human health. Dietary Cu is absorbed through the intestine, stored in the liver, and mobilized into the circulation; howe ... Full text Link to item Cite

beta-Arrestin-dependent activation of Ca(2+)/calmodulin kinase II after beta(1)-adrenergic receptor stimulation.

Journal Article J Cell Biol · May 3, 2010 Featured Publication Ca(2+)/calmodulin kinase II (CaMKII) plays an important role in cardiac contractility and the development of heart failure. Although stimulation of beta(1)-adrenergic receptors (ARs) leads to an increase in CaMKII activity, the molecular mechanism by which ... Full text Link to item Cite

Gene deletion screen for cardiomyopathy in adult Drosophila identifies a new notch ligand.

Journal Article Circ Res · April 16, 2010 Featured Publication RATIONALE: Drosophila has been recognized as a model to study human cardiac diseases. OBJECTIVE: Despite these findings, and the wealth of tools that are available to the fly community, forward genetic screens for adult heart phenotypes have been rarely pe ... Full text Link to item Cite

Cardiovascular phenotyping of the mouse heart using a 4D radial acquisition and liposomal Gd-DTPA-BMA.

Journal Article Magn Reson Med · April 2010 MR microscopy has enormous potential for small-animal cardiac imaging because it is capable of producing volumetric images at multiple time points to accurately measure cardiac function. MR has not been used as frequently as ultrasound to measure cardiac f ... Full text Link to item Cite

TRPC1 channels are critical for hypertrophic signaling in the heart.

Journal Article Circ Res · November 6, 2009 RATIONALE: Cardiac muscle adapts to increase workload by altering cardiomyocyte size and function resulting in cardiac hypertrophy. G protein-coupled receptor signaling is known to govern the hypertrophic response through the regulation of ion channel acti ... Full text Link to item Cite

Beta1-adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction.

Journal Article Am J Physiol Heart Circ Physiol · October 2009 The beta-adrenergic receptor (betaAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca(2+) homeostasis. We investigated the role of betaAR stimulation in augmenting cardiac function and its role in the a ... Full text Link to item Cite

Tnni3k modifies disease progression in murine models of cardiomyopathy.

Journal Article PLoS Genet · September 2009 The Calsequestrin (Csq) transgenic mouse model of cardiomyopathy exhibits wide variation in phenotypic progression dependent on genetic background. Seven heart failure modifier (Hrtfm) loci modify disease progression and outcome. Here we report Tnni3k (car ... Full text Link to item Cite

beta-Arrestin mediates beta1-adrenergic receptor-epidermal growth factor receptor interaction and downstream signaling.

Journal Article J Biol Chem · July 24, 2009 Featured Publication beta1-Adrenergic receptor (beta1AR) stimulation confers cardioprotection via beta-arrestin-de pend ent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothes ... Full text Link to item Cite

Decreased beta-adrenergic responsiveness following hypertrophy occurs only in cardiomyocytes that also re-express beta-myosin heavy chain.

Journal Article Eur J Heart Fail · July 2009 AIMS: Cardiac hypertrophy is associated with a reduction in the contractile response to beta-adrenergic stimulation, and with re-expression of foetal genes such as beta-myosin heavy chain (MHC). However, whether these two markers of pathology develop conco ... Full text Link to item Cite

An N-ethyl-N-nitrosourea mutagenesis recessive screen identifies two candidate regions for murine cardiomyopathy that map to chromosomes 1 and 15.

Journal Article Mamm Genome · May 2009 Featured Publication N-ethyl-N-nitrosourea (ENU) mutagenesis screens have been successful for identifying genes that affect important biological processes and diseases. However, for heart-related phenotypes, these screens have been employed exclusively for developmental phenot ... Full text Link to item Cite

Endogenous S-nitrosothiols protect against myocardial injury.

Journal Article Proc Natl Acad Sci U S A · April 14, 2009 Featured Publication Despite substantial evidence that nitric oxide (NO) and/or endogenous S-nitrosothiols (SNOs) exert protective effects in a variety of cardiovascular diseases, the molecular details are largely unknown. Here we show that following left coronary artery ligat ... Full text Link to item Cite

Distinct effects of tafazzin deletion in differentiated and undifferentiated mitochondria.

Journal Article Mitochondrion · April 2009 Tafazzin is a conserved mitochondrial protein that is required to maintain normal content and composition of cardiolipin. We used electron tomography to investigate the effect of tafazzin deletion on mitochondrial structure and found that cellular differen ... Full text Link to item Cite

Physiologic and cardiac roles of beta-arrestins.

Journal Article J Mol Cell Cardiol · March 2009 Beta-arrestin1 and beta-arrestin2 were initially identified by sequence homology to visual arrestins and by their ability to bind to and inactivate signaling of the beta-2-adrenergic receptor in a process known as desensitization. While the role of beta-ar ... Full text Link to item Cite

Receptor signaling pathways in heart failure: Transgenic mouse models

Journal Article · December 1, 2008 With increasing prevalence and high mortality, heart failure (HF) emerges as a major health problem. The heart often undergoes myocardial hypertrophy in response to increased load demand, and acute or chronic HF occurs when the heart acutely or gradually d ... Full text Cite

Beta-arrestin-mediated signaling in the heart.

Journal Article Circ J · November 2008 Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that beta-arrestin is also a signaling molecule capable of initiating its own G-protein-indepen ... Full text Link to item Cite

A role for the thromboxane receptor in L-NAME hypertension.

Journal Article Am J Physiol Renal Physiol · October 2008 Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on ... Full text Link to item Cite

Drosophila melanogaster as a model system for genetics of postnatal cardiac function.

Journal Article Drug Discov Today Dis Models · October 1, 2008 The fruit fly, Drosophila melanogaster, is an excellent model system that has a vast set of molecular tools and mutants to dissect the genetic pathways that are responsible for the normal and abnormal cardiac function. While the majority of studies have fo ... Full text Link to item Cite

Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation.

Journal Article Proc Natl Acad Sci U S A · September 23, 2008 Featured Publication Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also beta-arrestin-dependent signaling. One such beta-arrestin-mediated pathway uses the beta(1)-adrenergic receptor (be ... Full text Link to item Cite

Discordant on/off switching of gene expression in myocytes during cardiac hypertrophy in vivo.

Journal Article Proc Natl Acad Sci U S A · September 2, 2008 To determine whether the expression of cardiac genes changes in a graded manner or by on/off switching when cardiac myocytes change genetic programs in living animals, we have studied two indicator genes that change their expression oppositely in mouse bin ... Full text Link to item Cite

High oxygen prevents fetal lethality due to lack of catecholamines.

Journal Article Am J Physiol Regul Integr Comp Physiol · September 2008 The catecholamine norepinephrine is required for fetal survival, but its essential function is unknown. When catecholamine-deficient [tyrosine hydroxylase (Th) null] mouse fetuses die at embryonic day (E)13.5-14.5, they resemble wild-type (wt) fetuses expo ... Full text Link to item Cite

Beta-arrestins: multifunctional cellular mediators.

Journal Article Physiology (Bethesda) · February 2008 Initially thought to play a role only in G-protein-coupled receptor desensitization, beta-arrestins are ascribed with new roles such as scaffolding and signaling proteins by their own right. This review explores the many functions of beta-arrestins, with a ... Full text Link to item Cite

Increased myocardial contractility and enhanced exercise function in transgenic mice overexpressing either adenylyl cyclase 5 or 8.

Journal Article Basic Res Cardiol · January 2008 OBJECTIVE: ss-adrenergic receptors (ssARs) are powerful regulators of cardiac function in vivo, activating heterotrimeric G proteins and the effector molecule adenylyl cyclase (AC). Interestingly, cardiac-specific overexpression of different AC isoforms le ... Full text Link to item Cite

Reduced life span with heart and muscle dysfunction in Drosophila sarcoglycan mutants.

Journal Article Hum Mol Genet · December 1, 2007 In humans, genetically diverse forms of muscular dystrophy are associated with a disrupted sarcoglycan complex. The sarcoglycan complex resides at the muscle plasma membrane where it associates with dystrophin. There are six known sarcoglycan proteins in m ... Full text Link to item Cite

Left ventricular functional assessment in mice: feasibility of high spatial and temporal resolution ECG-gated blood pool SPECT.

Journal Article Radiology · November 2007 PURPOSE: To prospectively determine feasibility of evaluating murine left ventricular (LV) function with electrocardiographically (ECG)-gated blood pool single photon emission computed tomography (SPECT). MATERIALS AND METHODS: All animal studies had insti ... Full text Link to item Cite

Hypertension and albuminuria in chronic kidney disease mapped to a mouse chromosome 11 locus.

Journal Article Kidney Int · November 2007 Chronic kidney disease (CKD) is a key cause of hypertension and a potent independent risk for cardiovascular disease. Epidemiological studies suggest a strong genetic component determining susceptibility for renal disease and, by inference, the associated ... Full text Link to item Cite

Ankyrin-B syndrome: enhanced cardiac function balanced by risk of cardiac death and premature senescence.

Journal Article PLoS One · October 17, 2007 Here we report the unexpected finding that specific human ANK2 variants represent a new example of balanced human variants. The prevalence of certain ANK2 (encodes ankyrin-B) variants range from 2 percent of European individuals to 8 percent in individuals ... Full text Link to item Cite

Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection.

Journal Article J Clin Invest · September 2007 Featured Publication Deleterious effects on the heart from chronic stimulation of beta-adrenergic receptors (betaARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent adenylyl cyclase activation. Here, we identify a new s ... Full text Open Access Link to item Cite

Reversal of cardiac remodeling by modulation of adrenergic receptors: a new frontier in heart failure.

Journal Article Curr Opin Cardiol · September 2007 PURPOSE OF REVIEW: Heart failure is a common clinical syndrome, and despite intensive medical therapy it remains a leading cause of global morbidity and mortality. Pathological stimuli promote a general remodeling process in the heart. RECENT FINDINGS: Rec ... 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

Cardiac GPCRs: GPCR signaling in healthy and failing hearts.

Journal Article Biochim Biophys Acta · April 2007 G protein-coupled receptors (GPCRs) are widely implicated in human heart disease, making them an important target for cardiac drug therapy. The most commonly studied and clinically targeted cardiac GPCRs include the adrenergic, angiotensin, endothelin, and ... Full text Link to item Cite

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Journal Article Journal of the American College of Cardiology · March 13, 2007 Full text Cite

Cardiac micro-computed tomography for morphological and functional phenotyping of muscle LIM protein null mice.

Journal Article Mol Imaging · 2007 The purpose of this study was to investigate the use of micro-computed tomography (micro-CT) for morphological and functional phenotyping of muscle LIM protein (MLP) null mice and to compare micro-CT with M-mode echocardiography. MLP null mice and controls ... Link to item Cite

Heptahelical receptor signaling in heart failure

Conference Journal of Molecular and Cellular Cardiology · December 2006 Full text Cite

Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes.

Journal Article Proc Natl Acad Sci U S A · October 31, 2006 The G protein-coupled receptor kinases (GRKs) and beta-arrestins, families of molecules essential to the desensitization of G protein-dependent signaling via seven-transmembrane receptors (7TMRs), have been recently shown to also transduce G protein-indepe ... Full text Link to item Cite

Redefining heart failure: the utility of genomics.

Journal Article J Am Coll Cardiol · October 3, 2006 In this era of genomics, new technologies and the information that they generate have a wide range of potential applications to heart failure. Though there has not been widespread practical use of genomic information in everyday practice, there are many ex ... Full text Link to item Cite

Competitive displacement of phosphoinositide 3-kinase from beta-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling.

Journal Article Am J Physiol Heart Circ Physiol · October 2006 Adverse remodeling after myocardial infarction (MI) determines the progression of heart failure. Failing hearts are characterized by downregulation of beta-adrenergic receptor (beta-AR) signaling in part because of increased beta-AR kinase 1 activity. Our ... Full text Link to item Cite

Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function.

Journal Article Circ Res · August 18, 2006 Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which are converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (Ephx2, sEH). To examine the functional role of sEH in the heart, mice wi ... Full text Link to item Cite

Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice.

Journal Article J Clin Invest · August 2006 The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structu ... Full text Link to item Cite

Targeted inhibition of phosphoinositide 3-kinase activity as a novel strategy to normalize beta-adrenergic receptor function in heart failure.

Journal Article Vascul Pharmacol · August 2006 Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Normalization of betaAR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, sugg ... Full text Link to item Cite

Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction.

Journal Article J Clin Invest · June 2006 Featured Publication For over a century, there has been intense debate as to the reason why some cardiac stresses are pathological and others are physiological. One long-standing theory is that physiological overloads such as exercise are intermittent, while pathological overl ... Full text Link to item Cite

JNK1 is required to preserve cardiac function in the early response to pressure overload.

Journal Article Biochem Biophys Res Commun · May 19, 2006 Cardiac stress consistently activates c-Jun NH(2)-terminal kinase (JNK) pathways, however the role of different members of the JNK family is unclear. In this study, we applied pressure overload (TAC) in mice with selective deletion of the three JNK genes ( ... Full text Link to item Cite

Role of beta-adrenergic receptor signaling and desensitization in heart failure: new concepts and prospects for treatment.

Journal Article Expert Rev Cardiovasc Ther · May 2006 The use of beta-blockers to antagonize beta-adrenergic receptor signaling in the heart has become a standard method of treatment for heart failure, resulting in positive clinical outcomes alone and in conjunction with other modulators of cardiomyocyte cont ... Full text Link to item Cite

Agonist-stimulated beta-adrenergic receptor internalization requires dynamic cytoskeletal actin turnover.

Journal Article J Biol Chem · April 7, 2006 Stimulation of beta-adrenergic receptors (betaARs) leads to sequential recruitment of beta-arrestin, AP-2 adaptor protein, clathrin, and dynamin to the receptor complex, resulting in endocytosis. Whether a dynamic actin cytoskeleton is required for betaAR ... Full text Link to item Cite

Drosophila as a model for the identification of genes causing adult human heart disease.

Journal Article Proc Natl Acad Sci U S A · January 31, 2006 Featured Publication Drosophila melanogaster genetics provides the advantage of molecularly defined P-element insertions and deletions that span the entire genome. Although Drosophila has been extensively used as a model system to study heart development, it has not been used ... Full text Link to item Cite

Imaging methods for morphological and functional phenotyping of the rodent heart.

Journal Article Toxicol Pathol · 2006 Small animal imaging has a critical role in phenotyping, drug discovery, and in providing a basic understanding of mechanisms of disease. Translating imaging methods from humans to small animals is not an easy task. The purpose of this work is to compare t ... Full text Link to item Cite

NSAIDs and cardiovascular risk - Reply [2]

Journal Article Cell Metabolism · December 1, 2005 Full text Cite

When 7 transmembrane receptors are not G protein-coupled receptors.

Journal Article J Clin Invest · November 2005 Classically, 7 transmembrane receptors transduce extracellular signals by coupling to heterotrimeric G proteins, although recent in vitro studies have clearly demonstrated that they can also signal via G protein-independent mechanisms. However, the physiol ... Full text Open Access Link to item Cite

Prostacyclin protects against elevated blood pressure and cardiac fibrosis.

Journal Article Cell Metab · September 2005 Specific inhibitors of COX-2 have been associated with increased risk for cardiovascular complications. These agents reduce prostacyclin (PGI2) without affecting production of thromboxane (Tx) A2. While this abnormal pattern of eicosanoid generation has be ... Full text Link to item Cite

Defects in cardiomyocyte function: role of beta-adrenergic receptor dysfunction.

Journal Article Panminerva Med · September 2005 Heart failure is a common clinical syndrome characterized by increased levels of circulating catecholamines and extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Interestingly, whether dampening of betaAR signals is beneficial or det ... Link to item Cite

An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation.

Journal Article Proc Natl Acad Sci U S A · August 23, 2005 The identity of the cellular mechanisms through which nitroglycerin (glyceryl trinitrate, GTN) elicits nitric oxide (NO)-based signaling to dilate blood vessels remains one of the longest standing foci of investigation and sources of controversy in cardiov ... Full text Link to item Cite

Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis.

Journal Article Nat Cell Biol · August 2005 Featured Publication Phosphoinositide 3-kinase (PI(3)K) is a unique enzyme characterized by both lipid and protein kinase activities. Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internaliza ... Full text Link to item Cite

Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression.

Journal Article J Am Coll Cardiol · June 7, 2005 OBJECTIVES: Desensitization and down-regulation of beta-adrenergic receptors (betaARs) are prominent features of heart failure largely mediated by increased levels of betaAR kinase-1 (betaARK1). BACKGROUND: beta-adrenergic receptor kinase 1 interacts with ... Full text Link to item Cite

QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival.

Journal Article Mamm Genome · June 2005 The progression from myocardial hypertrophy to heart failure is a complex process, involving genetic and environmental factors. Elucidating the genetic components contributing to heart failure has been difficult, largely because of the heterogeneity of hum ... Full text Link to item Cite

Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex.

Journal Article Circulation · May 24, 2005 BACKGROUND: Desensitization and downregulation of myocardial beta-adrenergic receptors (betaARs) are initiated by the increase in betaAR kinase 1 (betaARK1) levels. By interacting with betaARK1 through the phosphoinositide kinase (PIK) domain, phosphoinosi ... Full text Link to item Cite

cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform.

Journal Article Am J Physiol Heart Circ Physiol · March 2005 Four isoforms of cardiac troponin T (cTnT), a protein essential for calcium-dependent myocardial force development, are expressed in the human; they differ in charge and length. Their expression is regulated developmentally and is affected by disease state ... Full text 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

Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy.

Journal Article Am J Physiol Heart Circ Physiol · February 2005 The goal of this study was to determine the role of estrogen receptor subtypes in the development of pressure overload hypertrophy in mice. Epidemiological studies have suggested gender differences in the development of hypertrophy and heart disease, but t ... Full text Link to item Cite

Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice.

Journal Article Cardiovasc Res · February 1, 2005 OBJECTIVE: Defects in myocardial mitochondrial structure and function have been associated with heart failure in humans and animal models. Mice lacking the muscle LIM protein (MLP) develop morphological and clinical signs resembling human dilated cardiomyo ... Full text Link to item Cite

Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo.

Journal Article J Biol Chem · January 7, 2005 The mitogen-activated protein kinases (MAPK) have been the subject of many studies to identify signaling pathways that promote cell survival or death. In cultured cardiac myocytes, p38 MAPK promotes cell survival or death depending on whether it is activat ... Full text Link to item Cite

Methods for the detection of altered beta-adrenergic receptor signaling pathways in hypertrophied hearts.

Journal Article Methods Mol Med · 2005 Beta-adrenergic receptor signaling, desensitization, and downregualtion are fundamental mechanisms that contribute to both normal and altered myocardial function. The development of pharmacological and biochemical assays has provided the ability to measure ... Full text Link to item Cite

Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I.

Journal Article Proc Natl Acad Sci U S A · December 28, 2004 Muscle-specific RING finger protein 1 (MuRF1) is a sarcomere-associated protein that is restricted to cardiac and skeletal muscle. In skeletal muscle, MuRF1 is up-regulated by conditions that provoke atrophy, but its function in the heart is not known. The ... Full text Link to item Cite

Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway.

Journal Article Circ Res · September 3, 2004 Human CYP2J2 is abundant in heart and active in the biosynthesis of epoxyeicosatrienoic acids (EETs); however, the functional role of this P450 and its eicosanoid products in the heart remains unknown. Transgenic mice with cardiomyocyte-specific overexpres ... Full text Link to item Cite

Network integration of the adrenergic system in cardiac hypertrophy.

Journal Article Cardiovasc Res · August 15, 2004 Adrenergic receptors play a pivotal role in regulating cardiac function in response to a constantly changing environment. Altered alpha and beta adrenergic receptor signaling in vivo is associated with cardiac hypertrophy and failure. This review focuses o ... 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

Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene.

Journal Article Proc Natl Acad Sci U S A · March 2, 2004 Several mouse models have already proved valuable for investigating hypertrophic responses to cardiac stress. Here, we characterize one caused by a well defined single copy transgene, RenTgMK, that genetically clamps plasma renin and thence angiotensin II ... Full text Link to item Cite

Role for thromboxane receptors in angiotensin-II-induced hypertension.

Journal Article Hypertension · February 2004 To evaluate the role of thromboxane in hypertension and its complications, we studied mice with targeted disruption of the TXA2 receptor gene in an angiotensin-II-dependent model of hypertension. To determine whether genetic background might alter the phys ... Full text Link to item Cite

The role of G-protein-coupled receptors in heart failure

Journal Article Drug Discovery Today: Disease Mechanisms · January 1, 2004 Central to the development of congestive heart failure is the role by G-protein-coupled receptors (GPCRs). The sympathetic nervous system stimulates GPCRs during periods of stress. Novel therapeutic approaches to heart failure are focused on key enzymes th ... Full text Cite

Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy.

Journal Article Hum Mol Genet · December 1, 2003 The variability in outcome of heart failure patients depends on a number of factors including differences in their genetic background. To identify novel genes that modify the human heart failure phenotype, we used a strategy of quantitative trait locus (QT ... Full text Link to item 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

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

Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure.

Journal Article J Clin Invest · October 2003 Featured Publication beta-Adrenergic receptor (betaAR) downregulation and desensitization are hallmarks of the failing heart. However, whether abnormalities in betaAR function are mechanistically linked to the cause of heart failure is not known. We hypothesized that downregul ... Full text Link to item Cite

Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo.

Journal Article Circulation · September 30, 2003 BACKGROUND: Although the renin-angiotensin and the beta-adrenergic systems are interrelated, a direct interaction between beta-adrenergic receptors (betaARs) and angiotensin II type 1 receptors (AT1Rs) has not been identified. METHODS AND RESULTS: Here, we ... Full text Link to item Cite

Protein kinase A and G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis through different pathways.

Journal Article J Biol Chem · September 12, 2003 Agonist-induced phosphorylation of beta-adrenergic receptors (beta ARs) by G protein-coupled receptor kinases (GRKs) results in their desensitization followed by internalization. Whether protein kinase A (PKA)-mediated phosphorylation of beta ARs, particul ... 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

Role of phosphoinositide 3-kinase in cardiac function and heart failure.

Journal Article Trends Cardiovasc Med · July 2003 Phosphoinositide 3-kinase (PI3K) belongs to a conserved family of lipid kinases that regulate many critical functions in the cell by generating 3'-phosphorylated phosphatidylinositols. Although PI3K has been the focus of intense study in various biologic p ... Full text Link to item Cite

Modifier genes and heart failure.

Journal Article Minerva Cardioangiol · April 2003 Recent progress in genomic applications have led to a better understanding of the relationship between genetic background and cardiovascular diseases such as heart failure. A considerable component of the variability in heart failure outcome is due to modi ... Link to item Cite

Impact of genetic polymorphisms on heart failure prognosis.

Journal Article Arch Mal Coeur Vaiss · March 2003 Recent progress in genomic applications have led to a better understanding of the relationship between genetic background and cardiovascular diseases such as heart failure. The broad variability in heart failure patient outcome is in part secondary to modi ... Link to item Cite

Pressure overload selectively up-regulates Ca2+/calmodulin-dependent protein kinase II in vivo.

Journal Article Mol Endocrinol · February 2003 Signals transduced by the multifunctional calcium/calmodulin-dependent protein kinases (CaMKs), have been suggested to regulate the development of hypertrophy. We address the role of the three multifunctional CaMKs, CaMK I, II, and IV, in this process usin ... Full text Link to item Cite

Sensing heart stress.

Journal Article Nat Med · January 2003 Full text Link to item Cite

Cardiac hypertrophy: role of G protein-coupled receptors.

Journal Article J Card Fail · December 2002 Cardiac myocytes respond to biomechanical stress by initiating cellular processes that lead to hypertrophy. Although cardiac hypertrophy is a response to increased stress on the heart, it is also associated with elevated plasma catecholamine levels and an ... 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

Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex.

Journal Article J Cell Biol · August 5, 2002 Internalization of beta-adrenergic receptors (betaARs) occurs by the sequential binding of beta-arrestin, the clathrin adaptor AP-2, and clathrin. D-3 phosphoinositides, generated by the action of phosphoinositide 3-kinase (PI3K) may regulate the endocytic ... Full text Link to item Cite

Heart size-independent analysis of myocardial function in murine pressure overload hypertrophy.

Journal Article Am J Physiol Heart Circ Physiol · June 2002 Pressure overload cardiac hypertrophy may be a compensatory mechanism to normalize systolic wall stress and preserve left ventricular (LV) function. To test this concept, we developed a novel in vivo method to measure myocardial stress (sigma)-strain (epsi ... Full text Link to item Cite

Genetic modifier loci affecting survival and cardiac function in murine dilated cardiomyopathy.

Journal Article Circulation · April 16, 2002 BACKGROUND: Understanding the role for genetic factors in human heart failure is difficult because environmental factors cannot be standardized and genetic variation is great. One approach to identify genes that modify disease outcome is to use mouse model ... 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

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

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

G-protein-coupled receptor function in heart failure.

Journal Article Cold Spring Harb Symp Quant Biol · 2002 Full text Link to item Cite

Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.

Journal Article Circulation · November 13, 2001 BACKGROUND: Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotr ... Full text Open Access Link to item Cite

Beta-adrenergic axis and heart disease.

Journal Article Trends Genet · October 2001 Beta-adrenergic receptors (beta-ARs) belong to a large family of G-protein-coupled receptors (GPCRs) that form the interface between the sympathetic nervous system and the cardiovascular system. The beta-AR signal system is one of the most powerful regulat ... Full text Link to item Cite

Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy.

Journal Article J Am Coll Cardiol · September 2001 OBJECTIVES: We sought to define the role of norepinephrine and epinephrine in the development of cardiac hypertrophy and to determine whether the absence of circulating catecholamines alters the activation of downstream myocardial signaling pathways. BACKG ... Full text Link to item Cite

G protein-coupled receptor signalling in in vivo cardiac overload.

Journal Article Acta Physiol Scand · September 2001 Cardiac myocytes respond to biomechanical stress by initiating cellular processes that lead to hypertrophy. Although cardiac hypertrophy is a response to increased stress on the heart, it is associated with elevated plasma catecholamine levels and an incre ... 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

Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias in heart failure.

Journal Article J Biol Chem · July 27, 2001 We investigated the cellular and molecular mechanisms underlying arrhythmias in heart failure. A genetically engineered mouse lacking the expression of the muscle LIM protein (MLP-/-) was used in this study as a model of heart failure. We used electrocardi ... Full text Link to item Cite

Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration.

Journal Article J Biol Chem · June 1, 2001 Agonist-dependent desensitization of the beta-adrenergic receptor requires translocation and activation of the beta-adrenergic receptor kinase1 by liberated Gbetagamma subunits. Subsequent internalization of agonist-occupied receptors occurs as a result of ... 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

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice.

Journal Article J Clin Invest · April 2001 Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac ... Full text 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

Cellular and functional defects in a mouse model of heart failure.

Journal Article Am J Physiol Heart Circ Physiol · December 2000 Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP(-/-)). The character and extent of the heart failure that occurs in MLP(-/-) mice were investigated using echocardiography and in vivo pressure-volume ... 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

Dilated cardiomyopathy in transgenic mice expressing a mutant A subunit of protein phosphatase 2A.

Journal Article Am J Physiol Heart Circ Physiol · September 2000 The protein phosphatase 2A (PP2A) holoenzyme consists of a catalytic subunit, C, and two regulatory subunits, A and B. The PP2A core enzyme is composed of subunits A and C. Both the holoenzyme and the core enzyme are similarly abundant in heart tissue. Tra ... Full text Link to item Cite

Enhanced cardiac function in transgenic mice expressing a Ca(2+)-stimulated adenylyl cyclase.

Journal Article Circ Res · April 14, 2000 The predominant functional adenylyl cyclases normally expressed in cardiac tissue and coupled to beta-adrenergic receptors are inhibited by micromolar Ca(2+) concentration. To modify the overall balance of activities, we have generated transgenic mice expr ... Full text 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

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

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

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

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

Role of β-adrenoceptor desensitization in heart failure

Journal Article Cardiovascular Drug Reviews · January 1, 1999 Heart failure is characterized by left ventricular dysfunction associated with a complex of symptoms that relate to inadequate perfusion of tissues and pulmonary congestion. When the heart is damaged by an insult, compensatory mechanisms mediated through a ... Full text 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

Targeted overexpression of phospholamban to mouse atrium depresses Ca2+ transport and contractility.

Journal Article J Mol Cell Cardiol · October 1998 Phospholamban is a small phosphoprotein regulator of the Ca2+-pump of cardiac sarcoplasmic reticulum. Dephosphorylated phospholamban inhibits the Ca2+-pump and depresses contractility, whereas phosphorylation of phospholamban by cAMP-activated mechanisms r ... Full text Link to item Cite

Effects of growth hormone and IGF-I on cardiac hypertrophy and gene expression in mice.

Journal Article Am J Physiol · August 1998 Cardiac hypertrophic and contractile responses were studied in mice administered growth hormone (GH) and insulin-like growth factor (IGF-I) (8 mg . kg-1 . day-1), alone or in combination (IGF-I/GH), for 2 wk. Also, changes in expression of selected left ve ... Full text 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

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

Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A.

Journal Article Proc Natl Acad Sci U S A · December 23, 1997 Natriuretic peptides, produced in the heart, bind to the natriuretic peptide receptor A (NPRA) and cause vasodilation and natriuresis important in the regulation of blood pressure. We here report that mice lacking a functional Npr1 gene coding for NPRA hav ... Full text Link to item 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

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

Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation.

Journal Article J Clin Invest · July 15, 1997 The Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2) plays a dominant role in lowering cytoplasmic calcium levels during cardiac relaxation and reduction of its activity has been linked to delayed diastolic relaxation in hypothyroid and failing hearts. T ... 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

A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program.

Journal Article Proc Natl Acad Sci U S A · June 10, 1997 During cardiac hypertrophy, the chief myocardial energy source switches from fatty acid beta-oxidation (FAO) to glycolysis-a reversion to fetal metabolism. The expression of genes encoding myocardial FAO enzymes was delineated in a murine ventricular press ... Full text 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

Force-frequency relations in the failing rabbit heart and responses to adrenergic stimulation.

Journal Article J Card Fail · March 1997 BACKGROUND: Recent experiments have documented the importance of beta-adrenergic regulation of the force-frequency relation (FFR) in the normal and failing heart. As in isolated human cardiac muscle, a descending limb of the FFR occurs at high frequencies ... Full text Link to item Cite

Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.

Journal Article Proc Natl Acad Sci U S A · January 7, 1997 Transgenic overexpression (40- to 100-fold) of the wild-type human beta2-adrenergic receptor in the hearts of mice leads to a marked increase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) acti ... 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

Uncoupling of G-protein coupled receptors in vivo: insights from transgenic mice.

Journal Article Adv Exp Med Biol · 1997 Heart failure is a problem of increasing importance in medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor down regulatio ... 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

[26]Molecular analysis of cardiac muscle diseases based on mouse genetics

Journal Article Methods in Molecular Genetics · December 1, 1996 Full text 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

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

Transthoracic echocardiography in models of cardiac disease in the mouse.

Journal Article Circulation · September 1, 1996 BACKGROUND: Transthoracic echocardiography (M-mode and Doppler) offers a noninvasive approach for in vivo evaluation of the mouse heart. The present study examines its usefulness for assessing the morphological/functional phenotype of the left ventricle (L ... Full text Link to item Cite

Apolipoprotein J/clusterin induction in myocarditis: A localized response gene to myocardial injury.

Journal Article Am J Pathol · June 1996 The function of apolipoprotein J (apoJ) is unknown, but it has been hypothesized to be cytoprotective. In the normal heart, abundant apoJ mRNA and protein are expressed in atrial myocytes; no expression is detected in ventricular myocytes. To provide clues ... Link to item Cite

Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the beta2-adrenergic receptor is associated with reduced phospholamban protein.

Journal Article J Clin Invest · April 1, 1996 To assess the effect of targeted myocardial beta-adrenergic receptor (AR) stimulation on relaxation and phospholamban regulation, we studied the physiological and biochemical alterations associated with overexpression of the human beta2-AR gene in transgen ... Full text Open Access Link to item Cite

Regulation of myocardial contractility: Insights from transgenic mice.

Journal Article Trends Cardiovasc Med · April 1996 Myocardial contraction occurs when calcium (Ca(2+)) is released from the sarcoplasmic reticulum, binding troponin C and allowing actin and myosin to cross link. Ca(2+) release and uptake is closely regulated by G protein-coupled β-adrenergic receptors thro ... Full text Link to item Cite

Transcriptional downregulation of a mitochondria!. fatty acid oxidation enzyme gene in response to ventricular pressure overload

Journal Article Journal of Investigative Medicine · January 1, 1996 Mitochondria! fatty acid oxidation (FAO) is the major source of energy in the adult mammalian heart. Previous studies have shown that energy production via the FAO pathway is reduced and glucose oxidation increased in the hypertrophiée) and failing heart. ... Cite

Is cardiac troponin C the length sensor in Starling's law of the heart? (multiple letters)

Journal Article Trends in Cardiovascular Medicine · January 1, 1996 Full text Cite

Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice.

Journal Article J Biol Chem · September 29, 1995 p21ras has been implicated in the hypertrophic response of cultured cardiac myocytes to defined growth stimuli. To determine if activation of ras-dependent intracellular signaling pathways is sufficient to induce in vivo hypertrophy, transgenic mice were c ... Full text Link to item Cite

Divergent pathways mediate the induction of ANF transgenes in neonatal and hypertrophic ventricular myocardium.

Journal Article J Clin Invest · September 1995 To determine whether similar or divergent pathways mediate atrial natriuretic factor (ANF) induction in neonatal and hypertrophied adult ventricular myocardium, and to assess whether studies using an in vitro model system of hypertrophy have fidelity to th ... 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

Heterogeneity of vasomotor response to acetylcholine along the human coronary artery.

Journal Article J Am Coll Cardiol · April 1995 OBJECTIVES: In view of the segmental occurrence of coronary atherosclerosis, we postulated that acetylcholine may cause heterogeneous vasomotion, depending on the extent of vessel analyzed, criteria for change in vessel caliber and dose of drug administere ... Full text Link to item Cite

Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor.

Journal Article Nature · March 16, 1995 G-protein-coupled receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling. But new evidence suggests a two-state model in which receptors are in equilibrium between the ... Full text Link to item Cite

Marked enhancement in myocardial function resulting from overexpression of a human beta-adrenergic receptor gene.

Journal Article J Thorac Cardiovasc Surg · February 1995 Transgenic mice with intense cardiac expression of a human beta-adrenergic receptor gene were engineered and shown to display marked improvements in baseline myocardial and left ventricular function. Heart/body weight ratios and histologic appearance were ... Full text Link to item Cite

Myocardial expression of a constitutively active alpha 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy.

Journal Article Proc Natl Acad Sci U S A · October 11, 1994 Transgenic mice were generated by using the alpha-myosin heavy chain promoter coupled to the coding sequence of a constitutively active mutant alpha 1B-adrenergic receptor (AR). These transgenic animals demonstrated cardiac-specific expression of this alph ... Full text Open Access Link to item Cite

ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice.

Journal Article Am J Physiol · June 1994 There is increasing evidence that the renin-angiotensin system may play a important role in cardiac hypertrophy. To assess the role of angiotensin II in the induction of cardiac hypertrophy, three groups of adult mice were subjected to left ventricular pre ... Full text Link to item Cite

Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor.

Journal Article Science · April 22, 1994 Transgenic mice were created with cardiac-specific overexpression of the beta 2-adrenergic receptor. This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; thes ... Full text Link to item Cite

Molecular and physiological alterations in murine ventricular dysfunction.

Journal Article Proc Natl Acad Sci U S A · March 29, 1994 The present study reports the development and characterization of a murine model of right ventricular dysfunction following graded constriction in the pulmonary artery via microsurgical approaches. To analyze in vivo ventricular function, a technique of x- ... Full text Link to item Cite

In vivo assessment of left ventricular remodelling after myocardial infarction by digital video contrast angiography in the rat.

Journal Article Cardiovasc Res · March 1994 OBJECTIVE: The aim was to develop a digital video contrast angiographic method for assessing global left ventricular function and volume in vivo in the rat and then to apply it to a study of ventricular remodelling after coronary occlusion, with and withou ... Full text Link to item Cite

Passive ventricular mechanics in tight-skin mice.

Journal Article Am J Physiol · March 1994 Although changes in the extracellular matrix have been associated with changes in ventricular compliance in certain diseased states, this relationship has not been entirely established. Accordingly, we studied passive ventricular mechanics in the tight-ski ... Full text Link to item Cite

Myocardial hypertrophy in the ischemic zone induced by exercise in rats after coronary reperfusion.

Journal Article Circulation · February 1993 BACKGROUND: Factors influencing left ventricular (LV) remodeling after coronary artery reperfusion, including adaptive changes in the infarcted region and the role of exercise, have not been well defined. The common application of early reperfusion by thro ... Full text Link to item Cite

In vivo murine cardiac hypertrophy: A novel model to identify genetic signaling mechanisms that activate an adaptive physiological response

Journal Article Circulation · January 1, 1993 Background. The signaling mechanisms that activate and regulate various alterations in cardiac gene expression during in vivo myocardial hypertrophy are largely unknown. Methods and Results. A model of left ventricular hypertrophy in the intact mouse was d ... Cite

Myocardial cell hypertrophy after myocardial infarction with reperfusion in dogs.

Journal Article Circulation · December 1992 BACKGROUND: The potential role of myocardial cell hypertrophy in the ischemic zone in the mechanism of late recovery of regional contractile function after myocardial infarction followed by reperfusion has not been examined. METHODS AND RESULTS: Eight chro ... Full text Link to item Cite

Myocardial function and transmural blood flow during coronary venous retroperfusion in pigs.

Journal Article Circulation · October 1992 BACKGROUND: The degree of recovery of regional myocardial contraction during coronary venous retroperfusion has not been well established, particularly in the absence of coronary collateral channels. Therefore, the maximal functional benefit attainable wit ... Full text Link to item Cite

Myosin light chain-2 luciferase transgenic mice reveal distinct regulatory programs for cardiac and skeletal muscle-specific expression of a single contractile protein gene.

Journal Article J Biol Chem · August 5, 1992 To examine the relationship between the cardiac and skeletal muscle gene programs, the current study employs the regulatory (phosphorylatable) myosin light chain (MLC-2) as a model system. Northern blotting, primer extension, and RNase protection studies d ... Link to item Cite

Enhancement of the force-frequency effect on myocardial contractility by adrenergic stimulation in conscious dogs.

Journal Article Circulation · August 1992 BACKGROUND: The influence of changes in heart rate on myocardial contractility (the force-frequency effect) differs under various experimental conditions, including the anesthetized versus the conscious state. METHODS AND RESULTS: To assess the influence o ... Full text Link to item Cite

Systolic and diastolic global right and left ventricular function assessment in small animals using an automated angiographic technique

Conference Proceedings - Computers in Cardiology, CIC 1992 · January 1, 1992 To assess left ventricular (LV) and right ventricular (RV) systolic and diastolic function in rats and mice, the authors developed a field-by-field angiographic analysis program. Interlaced video images were acquired on a videotape recorder under a constan ... Full text Cite

Effect of alpha-adrenergic stimulation on regional contractile function and myocardial blood flow with and without ischemia.

Journal Article Circulation · October 1991 BACKGROUND: The effect of alpha-adrenergic receptor activation on regional contractile function and transmural myocardial blood flow is controversial. Accordingly, the effects of selective alpha 1-(methoxamine) and alpha 2-(BHT 933) receptor stimulation on ... Full text Link to item Cite

Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy.

Journal Article Proc Natl Acad Sci U S A · September 15, 1991 To study the mechanisms that activate expression of the atrial natriuretic factor (ANF) gene during pressure-induced hypertrophy, we have developed and characterized an in vivo murine model of myocardial cell hypertrophy. We employed microsurgical techniqu ... Full text Link to item Cite

Long-term predictors of sudden and low output death in chronic congestive heart failure secondary to coronary artery disease.

Journal Article Am J Cardiol · December 1, 1989 Clinical, hemodynamic and neurohumoral variables in 238 patients with chronic congestive heart failure (CHF) secondary to coronary artery disease were analyzed to determine potential predictors of mortality in a large population and to allow analysis accor ... Full text Link to item Cite

Regulation of sugar transport in cultured diploid human skin fibroblasts.

Journal Article J Cell Physiol · September 1982 The regulation of hexose transport under glucose-starvation conditions was studied in cultured human skin fibroblasts. Glucose starvation enhanced the transport of 2-DG and 3-0-methyl-D-glucose (3-OMG) but not of L-glucose. Glucose-starvation enhanced tran ... Full text Link to item Cite