ArticleCirculation. Arrhythmia and electrophysiology2014
Pak1 is required to maintain ventricular Ca²⁺ homeostasis and electrophysiological stability through SERCA2a regulation in mice.
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Article in Circulation. Arrhythmia and electrophysiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 36 citations in OpenAlex.
- A Novel Pak1 Activator Ameliorates ER Stress for HFpEF Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Pak1 overexpression is associated with mild concentric cardiac remodeling and favorable systolic and diastolic functional indices in transgenic mice.Frontiers in cardiovascular medicine · 2026Article
- Cardiomyocyte Rac1 signaling in hypertrophy, arrhythmia, and cardiac stress adaptation.Journal of molecular and cellular cardiology plus · 2025Review
- Rac1 palmitoylation is required for cardiac stress adaptation and regulation of protein kinase A signaling.JCI insight · 2025Article
- p21-Activated Kinase 1 (Pak1) as an Element in Functional and Dysfunctional Interplay Among the Myocardium, Adipose Tissue, and Pancreatic Beta Cells.Comprehensive Physiology · 2025Review
- P21-activated kinase-1 signaling is required to preserve adipose tissue homeostasis and cardiac function.Molecular and cellular biochemistry · 2025Article
- Testosterone acts through the membrane protein GPRC6A to cause cardiac edema in zebrafish embryos.Development (Cambridge, England) · 2024Article
- Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.Circulation research · 2024Article
- Cardiac arrhythmogenesis: roles of ion channels and their functional modification.Frontiers in physiology · 2024Review
- Cardiomyocyte electrophysiology and its modulation: current views and future prospects.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Cardiac deficiency of P21-activated kinase 1 promotes atrial arrhythmogenesis in mice following adrenergic challenge.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Targeting p21-activated kinase 1 for development of a novel anti-arrhythmic drug class.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?Frontiers in cell and developmental biology · 2021Review
- PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPAROxidative medicine and cellular longevity · 2021Article
- Transcriptome signature of ventricular arrhythmia in dilated cardiomyopathy reveals increased fibrosis and activated TP53.Journal of molecular and cellular cardiology · 2020Article
- Sphingolipid Mediators of Myocardial Pathology.Journal of lipid and atherosclerosis · 2020Review
- Atrial Transcriptional Profiles of Molecular Targets Mediating Electrophysiological Function in Aging andFrontiers in physiology · 2019Article
- Modulation of store-operated calcium entry and nascent adhesion by p21-activated kinase 1.Experimental & molecular medicine · 2018Article
- The p21-activated kinase 1 (Pak1) signalling pathway in cardiac disease: from mechanistic study to therapeutic exploration.British journal of pharmacology · 2018Review
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Authors and funding
14 authors at 5 institutions in 3 countries.
Yanwen WangFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Hoyee TsuiFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Yunbo KeFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Ying ShiFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Yatong LiFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Laura DaviesFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Elizabeth J CartwrightFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Luigi VenetucciFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Henggui ZhangFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Derek A TerrarFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Christopher L-H HuangFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
R John SolaroFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.).
Xin WangFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.). ming.lei@pharm.ox.ac.uk xing.wang@manchester.ac.uk.
Ming LeiFrom the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.S., M.L.); Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (C.L.-H.H.). ming.lei@pharm.ox.ac.uk xing.wang@manchester.ac.uk.
University of Illinois Urbana-Champaign · USHuazhong University of Science and Technology · CNUniversity of Oxford · GBUnion Hospital · CNUniversity of Illinois Chicago · US
Funding
Sarcomeric Modifications and Progressive Cardiac MaladaptationP01HL062426 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI SOLARO, R JOHN · 2000 to 2020
$42.4MTroponin Mudulation in Heart FailureR01HL064035 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI SOLARO, R JOHN, WOLSKA, BEATA M. · 2000 to 2013
$4.7MBritish Heart Foundation FS/10/63/28374British Heart Foundation PG/09/052/27833British Heart Foundation PG/11/59/29006British Heart Foundation PG11/59/29006British Heart Foundation PG/12/21/29473British Heart Foundation PG/12/76/29852Medical Research Council G10002647Medical Research Council G1002082Medical Research Council G1002647NHLBI NIH HHS HL 064035NHLBI NIH HHS P01 HL 062426NHLBI NIH HHS P01 HL062426NHLBI NIH HHS R01 HL064035
Abstract
backgroundImpaired sarcoplasmic reticular Ca(2+) uptake resulting from decreased sarcoplasmic reticulum Ca(2+)-ATPase type 2a (SERCA2a) expression or activity is a characteristic of heart failure with its associated ventricular arrhythmias. Recent attempts at gene therapy of these conditions explored strategies enhancing SERCA2a expression and the activity as novel approaches to heart failure management. We here explore the role of Pak1 in maintaining ventricular Ca(2+) homeostasis and electrophysiological stability under both normal physiological and acute and chronic β-adrenergic stress conditions. METHODS AND
resultsMice with a cardiomyocyte-specific Pak1 deletion (Pak1(cko)), but not controls (Pak1(f/f)), showed high incidences of ventricular arrhythmias and electrophysiological instability during either acute β-adrenergic or chronic β-adrenergic stress leading to hypertrophy, induced by isoproterenol. Isolated Pak1(cko) ventricular myocytes correspondingly showed aberrant cellular Ca(2+) homeostasis. Pak1(cko) hearts showed an associated impairment of SERCA2a function and downregulation of SERCA2a mRNA and protein expression. Further explorations of the mechanisms underlying the altered transcriptional regulation demonstrated that exposure to control Ad-shC2 virus infection increased SERCA2a protein and mRNA levels after phenylephrine stress in cultured neonatal rat cardiomyocytes. This was abolished by the Pak1-knockdown in Ad-shPak1-infected neonatal rat cardiomyocytes and increased by constitutive overexpression of active Pak1 (Ad-CAPak1). We then implicated activation of serum response factor, a transcriptional factor well known for its vital role in the regulation of cardiogenesis genes in the Pak1-dependent regulation of SERCA2a.
conclusionsThese findings indicate that Pak1 is required to maintain ventricular Ca(2+) homeostasis and electrophysiological stability and implicate Pak1 as a novel regulator of cardiac SERCA2a through a transcriptional mechanism.
Indexed as
Adrenergic beta-AgonistsAnimalsCalciumCardiac Pacing, ArtificialCardiomegalyCells, CulturedDisease Models, AnimalElectrocardiographyGene Expression Regulation, EnzymologicHeart VentriclesHomeostasisIsoproterenolMaleMice, KnockoutMyocytes, Cardiacp21-Activated KinasesAdrenergic beta-AgonistsAtp2a2 protein, mouseAtp2a2 protein, ratCalciumIsoproterenolp21-Activated KinasesPak1 protein, mousePak1 protein, ratRNA, MessengerSarcoplasmic Reticulum Calcium-Transporting ATPasesarrhythmias, cardiaccalcium signalingP21-activated kinasessarcoplasmic reticulum Ca2+ ATPases
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