Scholars@Duke
Paul Brian Rosenberg

Paul Brian Rosenberg

Professor of Medicine
Medicine, Cardiology
paul.b.rosenberg@duke.edu
Duke Box 103031, Durham, NC 27710
GSRB2, Room 4021, Durham, NC 27710

Selected Publications

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice.

Journal Article J Clin Invest · February 1, 2024 Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle, where it is best known for its role in store-operated Ca2+ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized ... Full text Link to item Cite

APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

Journal Article J Clin Invest · January 16, 2024 Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and ... Full text Open Access Link to item Cite

VDAC2 as a novel target for heart failure: Ca2+ at the sarcomere, mitochondria and SR.

Journal Article Cell Calcium · June 2022 Despite a growing number of successful therapies, heart failure remains the most common cause of death and disability worldwide. Thus, new and novel therapeutic strategies are urgently needed. Mitochondria of cardiomyocytes generate ATP that is needed to p ... Full text Open Access Link to item Cite

Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass.

Journal Article Mol Metab · March 2022 OBJECTIVE: Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane endoplasmic/sarcoplasmic reticulum (E/SR) protein recognized for its role in a store operated Ca2+ entry (SOCE), an ancient and ubiquitous signaling pathway. Whereas STIM1 is ... Full text Open Access Link to item Cite

Rehabilitation Intervention in Older Patients With Acute Heart Failure With Preserved Versus Reduced Ejection Fraction.

Journal Article JACC Heart Fail · October 2021 OBJECTIVES: This study assessed for treatment interactions by ejection fraction (EF) subgroup (≥45% [heart failure with preserved ejection fraction (HFpEF); vs <45% [heart failure with reduced ejection fraction (HFrEF)]). BACKGROUND: The REHAB-HF trial sho ... Full text Open Access Link to item Cite

Desmin interacts with STIM1 and coordinates Ca2+ signaling in skeletal muscle.

Journal Article JCI Insight · September 8, 2021 Stromal interaction molecule 1 (STIM1), the sarcoplasmic reticulum (SR) transmembrane protein, activates store-operated Ca2+ entry (SOCE) in skeletal muscle and, thereby, coordinates Ca2+ homeostasis, Ca2+-dependent gene expression, and contractility. STIM ... Full text Open Access Link to item Cite

Relationship of physical function with quality of life in older patients with acute heart failure.

Journal Article J Am Geriatr Soc · July 2021 BACKGROUND: Older patients with acute decompensated heart failure (ADHF) have severely impaired physical function (PF) and quality of life (QOL). However, relationships between impairments in PF and QOL are unknown but are relevant to clinical practice and ... Full text Open Access Link to item Cite

SOCE in the cardiomyocyte: the secret is in the chambers.

Journal Article Pflugers Arch · March 2021 Store-operated Ca2+ entry (SOCE) is an ancient and ubiquitous Ca2+ signaling pathway that is present in virtually every cell type. Over the last two decades, many studies have implicated this non-voltage dependent Ca2+ entry pathway in cardiac physiology. ... Full text Open Access Link to item 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

STIM1-Ca2+ signaling in coronary sinus cardiomyocytes contributes to interatrial conduction.

Journal Article Cell Calcium · May 2020 Pacemaker action potentials emerge from the sinoatrial node (SAN) and rapidly propagate through the atria to the AV node via preferential conduction pathways, including one associated with the coronary sinus. However, few distinguishing features of these t ... Full text Open Access Link to item Cite

A Case of Rare Inherited Restrictive Cardiomyopathy With Severe Biatrial Enlargement.

Journal Article JACC Case Rep · December 2019 We describe a case of inherited restrictive cardiomyopathy in a patient presenting with severe biatrial enlargement. We review the evaluation and management of restrictive cardiomyopathy with a focus on genetic etiologies. (Level of Difficulty: Intermediat ... Full text Open Access Link to item Cite

SOCE and STIM1 signaling in the heart: Timing and location matter.

Journal Article Cell Calcium · January 2019 Store operated Ca2+ entry (SOCE) is an ancient and ubiquitous Ca2+ signaling pathway discovered decades ago, but the function of SOCE in human physiology is only now being revealed. The relevance of this pathway to striated muscle was solidified with the d ... Full text Open Access 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

Trends and outcomes of cardiac transplantation from donors dying of drug intoxication.

Journal Article Am Heart J · May 2018 BACKGROUND: Deaths from drug intoxication have increased in the United States but outcomes of recipients of orthotopic heart transplantation (OHT) from these donors are not well characterized. METHODS: We performed a retrospective analysis of the United Ne ... Full text Link to item Cite

Strategies for supporting intervention fidelity in the rehabilitation therapy in older acute heart failure patients (REHAB-HF) trial.

Journal Article Contemp Clin Trials · January 2018 INTRODUCTION: Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in older adults. Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial is a multi-site clinical trial to determine if physical rehabilita ... Full text Link to item Cite

Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects.

Journal Article Sci Signal · October 10, 2017 Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are pre ... Full text Open Access Link to item Cite

The role of STIM1 and SOCE in smooth muscle contractility.

Journal Article Cell Calcium · May 2017 Contraction is a central feature for skeletal, cardiac and smooth muscle; this unique feature is largely dependent on calcium (Ca2+) signaling and therefore maintenance of internal Ca2+ stores. Stromal interaction molecule 1 (STIM1) is a single-pass transm ... Full text Link to item Cite

Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial: Design and rationale.

Journal Article Am Heart J · March 2017 BACKGROUND: Acute decompensated heart failure (ADHF) is a leading cause of hospitalization in older persons in the United States. Reduced physical function and frailty are major determinants of adverse outcomes in older patients with hospitalized ADHF. How ... Full text Link to item Cite

Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity.

Journal Article Cardiooncology · 2017 BACKGROUND: Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether ... Full text Open Access Link to item Cite

The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia.

Journal Article Arterioscler Thromb Vasc Biol · May 2016 OBJECTIVE: Vascular smooth muscle cell (SMC) migration is regulated by cytoskeletal remodeling as well as by certain transient receptor potential (TRP) channels, nonselective cation channels that modulate calcium influx. Proper function of multiple subfami ... Full text Open Access Link to item Cite

Canonical transient receptor potential 3 channels activate NF-κB to mediate allergic airway disease via PKC-α/IκB-α and calcineurin/IκB-β pathways.

Journal Article FASEB J · January 2016 The purpose of this study was to determine the role of canonical transient receptor potential 3 (TRPC3) channel in allergen-induced airway disease (AIAD) and its underlying signaling mechanisms. The procedures included (1) intravenous injection of lentivir ... Full text Link to item Cite

STIM1-Ca2+ signaling modulates automaticity of the mouse sinoatrial node.

Conference Proc Natl Acad Sci U S A · October 13, 2015 Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca(2+) release from internal Ca(2+) s ... Full text Link to item Cite

STIM1 enhances SR Ca2+ content through binding phospholamban in rat ventricular myocytes.

Journal Article Proc Natl Acad Sci U S A · August 25, 2015 In ventricular myocytes, the physiological function of stromal interaction molecule 1 (STIM1), an endo/sarcoplasmic reticulum (ER/SR) Ca(2+) sensor, is unclear with respect to its cellular localization, its Ca(2+)-dependent mobilization, and its action on ... Full text Open Access Link to item Cite

Comparison of 2-Year Outcomes of Extended Criteria Cardiac Transplantation Versus Destination Left Ventricular Assist Device Therapy Using Continuous Flow.

Journal Article Am J Cardiol · August 15, 2015 Alternatives have emerged for patients ineligible for cardiac transplantation under standard criteria. The purpose of our study was to compare outcomes in patients ineligible for cardiac transplantation under standard criteria, treated either with extended ... Full text Link to item Cite

Gq signaling causes glomerular injury by activating TRPC6.

Journal Article J Clin Invest · May 2015 Familial forms of focal segmental glomerulosclerosis (FSGS) have been linked to gain-of-function mutations in the gene encoding the transient receptor potential channel C6 (TRPC6). GPCRs coupled to Gq signaling activate TRPC6, suggesting that Gq-dependent ... Full text Link to item Cite

TRP Channels in Cardiovascular Disease

Journal Article · April 8, 2015 Transient receptor potential (TRP) channels comprise a large superfamily of channels activated under conditions associated with cellular stress including stretch, neurohormonal signaling, hypoxia, and oxidative stress. Although often considered to be opera ... Full text Cite

MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function.

Journal Article Circ Res · January 30, 2015 RATIONALE: A major goal for the treatment of heart tissue damaged by cardiac injury is to develop strategies for restoring healthy heart muscle through the regeneration and repair of damaged myocardium. We recently demonstrated that administration of a spe ... Full text Link to item Cite

Skeletal muscle store-operated Ca2+ entry and STIM/Orai signaling in skeletal muscle

Chapter · November 1, 2013 In skeletal muscle, Ca2+ release from intracellular stores triggers actomyosin cross-bridge formation to generate and modulate contractile force, but myocytes also use Ca2+ signaling as a way to sense and respond to changes in workload to alter gene expres ... Full text Cite

Ten-year experience with extended criteria cardiac transplantation.

Journal Article Circ Heart Fail · November 2013 BACKGROUND: Extended criteria cardiac transplant (ECCT) programs expand the transplant pool by matching donors and recipients typically excluded from the transplant process because of age or comorbidity. There is a paucity of data examining long-term outco ... Full text Link to item Cite

Pdx-1 activates islet α- and β-cell proliferation via a mechanism regulated by transient receptor potential cation channels 3 and 6 and extracellular signal-regulated kinases 1 and 2.

Journal Article Mol Cell Biol · October 2013 The homeodomain transcription factor Pdx-1 has important roles in pancreatic development and β-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell rep ... Full text Link to item Cite

Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.

Journal Article J Biol Chem · August 9, 2013 Recent studies have shown that the pyruvate-isocitrate cycling pathway, involving the mitochondrial citrate/isocitrate carrier and the cytosolic NADP-dependent isocitrate dehydrogenase (ICDc), is involved in control of glucose-stimulated insulin secretion ... Full text Link to item Cite

Calcium flux and endothelial dysfunction during acute lung injury: a STIMulating target for therapy.

Journal Article J Clin Invest · March 2013 Bacterial pathogen-associated molecular pattern molecules (PAMPs) such as LPS activate the endothelium and can lead to lung injury, but the signaling pathways mediating endothelial injury remain incompletely understood. In a recent issue of the JCI, Gandhi ... Full text Link to item Cite

Cytoskeletal regulation of TRPC channels in the cardiorenal system.

Journal Article Curr Hypertens Rep · December 2012 Transient receptor potential canonical (TRPC) channels have been implicated in several aspects of cardiorenal physiology including regulation of blood pressure, vasoreactivity, vascular remodeling, and glomerular filtration. Gain and loss of function studi ... Full text Link to item Cite

STIM1-Ca(2+) signaling is required for the hypertrophic growth of skeletal muscle in mice.

Journal Article Mol Cell Biol · August 2012 Immediately after birth, skeletal muscle must undergo an enormous period of growth and differentiation that is coordinated by several intertwined growth signaling pathways. How these pathways are integrated remains unclear but is likely to involve skeletal ... Full text Open Access Link to item Cite

MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.

Journal Article Circ Res · May 25, 2012 RATIONALE: Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas ... Full text Link to item Cite

Dynamic regulation of sarcoplasmic reticulum Ca(2+) stores by stromal interaction molecule 1 and sarcolipin during muscle differentiation.

Journal Article Dev Dyn · April 2012 During muscle development, the sarco/endoplasmic reticulum (SR/ER) undergoes remodeling to establish a specialized internal Ca(2+) store for muscle contraction. We hypothesized that store operated Ca(2+) entry (SOCE) is required to fill Ca(2+) stores and i ... Full text Link to item Cite

186 Long Term Mechanical Circulatory Support: What Are the Final Options?

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

Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts.

Journal Article Circ Res · September 16, 2011 RATIONALE: Fibroblast growth factor homologous factors (FHFs), a subfamily of fibroblast growth factors (FGFs) that are incapable of functioning as growth factors, are intracellular modulators of Na(+) channels and have been linked to neurodegenerative dis ... Full text Link to item Cite

The role of store-operated calcium influx in skeletal muscle signaling.

Journal Article Cell Calcium · May 2011 In cardiac and skeletal muscle Ca(2+) release from intracellular stores triggers actomyosin cross-bridge formation and the generation of contractile force. In the face of large fluctuations of intracellular calcium ([Ca(2+)](i)) that occur with contractile ... Full text Link to item Cite

TRPC6 enhances angiotensin II-induced albuminuria.

Journal Article J Am Soc Nephrol · March 2011 Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understo ... 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

Mechanosensitive channels in striated muscle and the cardiovascular system: not quite a stretch anymore.

Journal Article J Cardiovasc Pharmacol · August 2009 Stretch-activated or mechanosensitive channels transduce mechanical forces into ion fluxes across the cell membrane. These channels have been implicated in several aspects of cardiovascular physiology including regulation of blood pressure, vasoreactivity, ... Full text Link to item Cite

Calcium entry in skeletal muscle.

Journal Article J Physiol · July 1, 2009 Full text Link to item Cite

Hypoxia reprograms calcium signaling and regulates myoglobin expression.

Journal Article Am J Physiol Cell Physiol · March 2009 Myoglobin is an oxygen storage molecule that is selectively expressed in cardiac and slow-twitch skeletal muscles that have a high oxygen demand. Numerous studies have implicated hypoxia in the regulation of myoglobin expression as an adaptive response to ... Full text Link to item Cite

Gq-dependent signaling upregulates COX2 in glomerular podocytes.

Journal Article J Am Soc Nephrol · November 2008 Accumulating evidence suggests that upregulation of cyclooxygenase 2 (COX2) in glomerular podocytes promotes podocyte injury. Because Gq signaling activates calcineurin and calcineurin-dependent mechanisms are known to mediate COX2 expression, this study i ... Full text Link to item Cite

STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle.

Journal Article Nat Cell Biol · June 2008 It is now well established that stromal interaction molecule 1 (STIM1) is the calcium sensor of endoplasmic reticulum stores required to activate store-operated calcium entry (SOC) channels at the surface of non-excitable cells. However, little is known ab ... Full text Link to item Cite

Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity.

Journal Article Mol Cell Biol · April 2008 Transient receptor potential (TRP) channels are nonselective cation channels, several of which are expressed in striated muscle. Because the scaffolding protein Homer 1 has been implicated in TRP channel regulation, we hypothesized that Homer proteins play ... Full text Link to item 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

Topical anesthesia with EMLA reduces pain during endomyocardial biopsy: a randomized trial.

Journal Article J Heart Lung Transplant · September 2006 Cardiac transplant recipients often anticipate and suffer varying degrees of discomfort during surveillance endomyocardial biopsy (EMBx). We performed a randomized, blinded, placebo-controlled trial to determine whether topical anesthetic was associated wi ... Full text Link to item Cite

Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy.

Journal Article Circ Res · March 3, 2006 Hypertrophic cardiomyopathy (HCM) is the most common form of sudden death in young competitive athletes. However, exercise has also been shown to be beneficial in the setting of other cardiac diseases. We examined the ability of voluntary exercise to preve ... Full text Link to item Cite

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Conference The Journal of Heart and Lung Transplantation · February 2006 Full text Cite

Implantable left ventricular assist devices: new hope for patients with end-stage heart failure.

Journal Article N C Med J · 2006 INTRODUCTION: Recently, the Food and Drug Administration approved implantable left ventricular assist devices (LVAD) as destination therapy (DT) for end-stage heart failure patients who are ineligible for cardiac transplantation. OBJECTIVE AND STUDY DESIGN ... Link to item Cite

Homer modulates NFAT-dependent signaling during muscle differentiation.

Journal Article Dev Biol · November 15, 2005 While changes in intracellular calcium are well known to influence muscle contraction through excitation contraction coupling, little is understood of the calcium signaling events regulating gene expression through the calcineurin/NFAT pathway in muscle. H ... Full text Link to item Cite

Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation.

Journal Article J Heart Lung Transplant · September 2005 BACKGROUND: Cyclosporine (CsA) is frequently initiated as induction therapy in patients undergoing orthotopic heart transplantation, but our experience has identified a significant rate of post-operative renal dysfunction. We therefore devised a renal-spar ... Full text Link to item Cite

Ryanodine receptors in muscarinic receptor-mediated bronchoconstriction.

Journal Article J Biol Chem · July 15, 2005 Ryanodine receptors (RyRs), intracellular calcium release channels essential for skeletal and cardiac muscle contraction, are also expressed in various types of smooth muscle cells. In particular, recent studies have suggested that in airway smooth muscle ... Full text Link to item Cite

A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.

Journal Article Science · June 17, 2005 Focal and segmental glomerulosclerosis (FSGS) is a kidney disorder of unknown etiology, and up to 20% of patients on dialysis have been diagnosed with it. Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene o ... Full text Link to item Cite

Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway.

Journal Article J Biol Chem · May 20, 2005 Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) promotes mitochondrial biogenesis and slow fiber formation in skeletal muscle. We hypothesized that activation of the p38 mitogen-activated protein kinase (MAPK) pathway in r ... Full text Link to item Cite

Mitochondrial dysfunction and heart disease

Journal Article Mitochondrion · September 1, 2004 Several inherited and acquired disorders of mitochondria lead to defects in cardiac function as reflected in exercise intolerance, arrhythmias and heart failure. Manifestations of mitochondrial dysfunction is reflected in the abnormal mitochondrial prolife ... Full text Cite

TRPC3 channels confer cellular memory of recent neuromuscular activity.

Journal Article Proc Natl Acad Sci U S A · June 22, 2004 Skeletal muscle adapts to different patterns of motor nerve activity by alterations in gene expression that match specialized properties of contraction, metabolism, and muscle mass to changing work demands (muscle plasticity). Calcineurin, a calcium/calmod ... Full text Link to item Cite

Tamoxifen and tamoxifen ethyl bromide induce apoptosis in acutely damaged mammary epithelial cells through modulation of AKT activity.

Journal Article Oncogene · May 6, 2004 Normal human mammary epithelial cells (HMECs), unlike estrogen receptor-positive (ER+) breast cancers, typically express low nuclear levels of ER (ER-'poor'). We previously demonstrated that 1.0 microM tamoxifen (Tam) induced apoptosis in ER-'poor' HMECs a ... Full text Link to item Cite

Cardiac transplantation at Duke University Medical Center.

Journal Article Clin Transpl · 2004 Since beginning cardiac transplantation in 1985, Duke University Medical Center has performed 485 de novo heart transplants in adult recipients. Our program has broadened the access of patients to transplantation through the aggressive use of ventricular a ... Link to item Cite

Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway.

Journal Article EMBO J · November 15, 2001 Gene expression in skeletal muscles of adult vertebrates is altered profoundly by changing patterns of contractile work. Here we observed that the functional activity of MEF2 transcription factors is stimulated by sustained periods of endurance exercise or ... Full text Link to item Cite

Noninvasive assessment of hemodynamics: an emphasis on bioimpedance cardiography.

Journal Article Curr Opin Cardiol · May 2000 Evaluation of the hemodynamic response in heart failure is a useful adjunct in clinical management. Invasive monitoring has been the accepted gold standard of hemodynamic assessment but carries with it significant associated risks. Noninvasive hemodynamic ... Full text Link to item Cite