Advertisement
Canadian Journal of Cardiology

Cardiac-Specific Overexpression of Caveolin-1 in Rats With Ischemic Cardiomyopathy Improves Arrhythmogenicity and Cardiac Remodelling

  • Shu-jie Wu
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Rui-lin He
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Lin Zhao
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Xiao-yu Yu
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Yi-na Jiang
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Xuan Guan
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Qiao-ying Chen
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Fang-fang Ren
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Zuo-yi Xie
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Lian-pin Wu
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
  • Li Lei
    Correspondence
    Corresponding author: Dr Li Lei, Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Xueyuan west load 109, Wenzhou, Zhejiang, China 325027. Tel./fax: +8618858700795.
    Affiliations
    Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China
    Search for articles by this author
Published:October 11, 2022DOI:https://doi.org/10.1016/j.cjca.2022.10.005

      Abstract

      Background

      Ischemic cardiomyopathy (ICM) is associated with electrical and structural remodelling, leading to arrhythmias. Caveolin-1 (Cav1) is a membrane protein involved in the pathogenesis of ischemic injury. Cav1 deficiency has been associated with arrhythmogenicity. The current study aimed to determine how Cav1 overexpression inhibits arrhythmias and cardiac remodelling in ICM.

      Methods

      ICM was modelled using left anterior descending (LAD) artery ligation for 4 weeks. Cardiac-specific Cav1 overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodelling were investigated using the intramyocardial injection of an adeno-associated virus serotype 9 (AAV-9) system, carrying a specific sequence expressing Cav1 (AAVCav1) under the cardiac troponin T (cTnT) promoter.

      Results

      Cav1 overexpression decreased susceptibility to arrhythmias by upregulating gap junction connexin 43 (CX43) and reducing spontaneous irregular proarrhythmogenic Ca2+ waves in ventricular cardiomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca2+ cycling through normalizing Ca2+-handling protein levels and improving Ca2+ homeostasis. Masson stain and immunoblotting revealed that the deposition of excessive fibrosis was attenuated by Cav1 overexpression, inhibiting the transforming growth factor-β (TGF-β)/Smad2 signalling pathway. Coimmunoprecipitation assays demonstrated that the interaction between Cav1 and cSrc modulated CX43 expression and Ca2+-handling protein levels.

      Conclusions

      Cardiac-specific overexpression of Cav1 attenuated ventricular arrhythmia, improved Ca2+ cycling, and attenuated cardiac remodelling. These effects were attributed to modulation of CX43, normalized Ca2+-handling protein levels, improved Ca2+ homeostasis, and attenuated cardiac fibrosis.

      Résumé

      Contexte

      La cardiomyopathie ischémique (CMI) est associée à un remodelage électrique et structurel menant à des arythmies. La cavéoline-1 (Cav1) est une protéine membranaire impliquée dans la pathogenèse des lésions ischémiques. Un déficit en Cav1 est associé à l’arythmogénicité. La présente étude visait à déterminer comment la surexpression de Cav1 inhibe les arythmies et le remodelage cardiaque dans un contexte de CMI.

      Méthodologie

      La CMI a été modélisée par ligature de l’artère antérieure gauche descendante pendant quatre semaines. La surexpression cardiospécifique de Cav1 en cas de CMI et son effet sur les arythmies, le couplage excitation-contraction et le remodelage cardiaque ont été étudiés après l’injection intramyocardique d’un vecteur viral adénoassocié de sérotype 9 (AAV-9) portant une séquence spécifique exprimant Cav1 (AAVCav1), qui est régulée par le promoteur de la troponine T cardiaque (cTnT).

      Résultats

      La surexpression de Cav1 a limité la propension aux arythmies en régulant positivement la protéine de jonction communicante Cx43 (connexine 43) et en réduisant les ondes calciques spontanées et irrégulières proarythmogènes dans les cardiomyocytes ventriculaires. Elle a aussi atténué l’hypocontractilité induite par les lésions ischémiques en améliorant le cycle calcique grâce à la normalisation des concentrations de calciprotéines et l’amélioration de l’homéostasie calcique. La coloration trichromique de Masson et l’immunobuvardage ont révélé que le dépôt excessif de collagène (fibrose) était atténué par la surexpression de Cav1, inhibant la voie de signalisation Smad2 induite par le facteur de croissance transformant β (TGF-β). Les données obtenues par co-immunoprécipitation ont démontré que l’interaction entre Cav1 et cSrc modulait l’expression de Cx43 et les concentrations de calciprotéines.

      Conclusions

      La surexpression cardiospécifique de Cav1 a atténué l’arythmie ventriculaire, amélioré le cycle calcique et diminué le remodelage cardiaque. Ces effets ont été attribués à la modulation de la protéine Cx43, à la normalisation des concentrations de calciprotéines, à l’amélioration de l’homéostasie calcique et à l’atténuation de la fibrose cardiaque.

      Graphical abstract

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Raj P.
        • Zieroth S.
        • Netticadan T.
        An overview of the efficacy of resveratrol in the management of ischemic heart disease.
        Ann NY Acad Sci. 2015; 1348: 55-67
        • Huikuri H.
        • Castellanos A.
        • Myerburg R.J.
        Sudden death due to cardiac arrhythmias.
        N Engl J Med. 2001; 345: 1473-1482
        • Mollenhauer M.
        • Friedrichs K.
        • Lange M.
        • et al.
        Myeloperoxidase mediates postischemic arrhythmogenic ventricular remodeling.
        Circ Res. 2017; 121: 56-70
        • Rutledge C.
        • Ng F.S.
        • Sulkin M.S.
        • et al.
        c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction.
        J Am Coll Cardiol. 2014; 63: 928-934
        • Nademanee K.
        • Raju H.
        • de Noronha S.V.
        • et al.
        Fibrosis, connexin-43, and conduction abnormalities in the brugada syndrome.
        J Am Coll Cardiol. 2015; 66: 1976-1986
        • Frangogiannis N.
        Cardiac fibrosis.
        Cardiovasc Res. 2021; 117: 1450-1488
        • Thireau J.
        • Karam S.
        • Fauconnier J.
        • et al.
        Functional evidence for an active role of B-type natriuretic peptide in cardiac remodelling and pro-arrhythmogenicity.
        Cardiovasc Res. 2012; 95: 59-68
        • Thireau J.
        • Karam S.
        • Roberge S.
        • et al.
        Beta-adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure?.
        Heart. 2014; 100: 833-841
        • Bers D.
        Altered cardiac myocyte Ca regulation in heart failure.
        Physiology (Bethesda). 2006; 21: 380-387
        • Hallstrom A.
        • Pratt C.M.
        • Greene H.L.
        • et al.
        Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial.
        J Am Coll Cardiol. 1995; 25: 1250-1257
        • Marks A.
        Calcium cycling proteins and heart failure: mechanisms and therapeutics.
        J Clin Invest. 2013; 123: 46-52
        • Cohen A.
        • Hnasko R.
        • Schubert W.
        • Lisanti M.P.
        Role of caveolae and caveolins in health and disease.
        Physiol Rev. 2004; 84: 1341-1379
        • Jasmin J.
        • Rengo G.
        • Lymperopoulos A.
        • et al.
        Caveolin-1 deficiency exacerbates cardiac dysfunction and reduces survival in mice with myocardial infarction.
        Am J Physiol Heart Circ Physiol. 2011; 300: H1274-H1281
        • Miyasato S.
        • Loeffler J.
        • Shohet R.
        • Zhang J.
        • Lindsey M.
        • Le Saux C.J.
        Caveolin-1 modulates TGF-beta1 signaling in cardiac remodeling.
        Matrix Biol. 2011; 30: 318-329
        • Yang K.
        • Rutledge C.A.
        • Mao M.
        • et al.
        Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase.
        Circ Arrhythm Electrophysiol. 2014; 7: 701-710
        • Severs N.
        Gap junction remodeling in heart failure.
        J Card Fail. 2002; 8: S293-S299
        • Wu S.
        • Li Y.C.
        • Shi Z.W.
        • et al.
        Alteration of cholinergic anti-inflammatory pathway in rat with ischemic cardiomyopathy-modified electrophysiological function of heart.
        J Am Heart Assoc. 2017; 6e006510
        • Daniel E.
        • Eteraf T.
        • Sommer B.
        • Cho W.J.
        • Elyazbi A.
        The role of caveolae and caveolin 1 in calcium handling in pacing and contraction of mouse intestine.
        J Cell Mol Med. 2009; 13: 352-364
        • Cheng X.
        • Jaggar J.H.
        Genetic ablation of caveolin-1 modifies Ca2+ spark coupling in murine arterial smooth muscle cells.
        Am J Physiol Heart Circ Physiol. 2006; 290: H2309-H2319
        • Litwin S.
        • Katz S.E.
        • Morgan J.P.
        • Douglas P.S.
        Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat.
        Circulation. 1994; 89: 345-354
        • Nishina T.
        • Nishimura K.
        • Yuasa S.
        • et al.
        Initial effects of the left ventricular repair by plication may not last long in a rat ischemic cardiomyopathy model.
        Circulation. 2001; 104: I241-I245
        • Hou Z.
        • Qin X.
        • Hu Y.
        • et al.
        Longterm exercise-derived exosomal miR-342-5p: a novel exerkine for cardioprotection.
        Circ Res. 2019; 124: 1386-1400
        • Nguyen T.E.S.E.
        • Rouleau J.L.
        Postinfarction survival and inducibility of ventricular arrhythmias in the spontaneously hypertensive rat effects of ramipril and hydralazine.
        Circulation. 1998; 98: 2074-2080
        • Cardinal R.V.M.
        • Shenasa M.
        • Roberge F.
        • Page P.
        • Hélie F.
        • Savard P.
        Anisotropic conduction and functional dissociation of ischemic tissue during reentrant ventricular tachycardia in canine myocardial infarction.
        Circulation. 1988; 77: 1162-1176
        • Yu J.
        • Zhang H.F.
        • Wu F.
        • et al.
        Insulin improves cardiomyocyte contractile function through enhancement of SERCA2a activity in simulated ischemia/reperfusion.
        Acta Pharmacol Sin. 2006; 27: 919-926
        • Scherer P.
        • Lewis R.Y.
        • Volonte D.
        • et al.
        Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo.
        J Biol Chem. 1997; 272: 29337-29346
        • Sonveaux P.
        • Martinive P.
        • DeWever J.
        • et al.
        Caveolin-1 expression is critical for vascular endothelial growth factor-induced ischemic hindlimb collateralization and nitric oxide-mediated angiogenesis.
        Circ Res. 2004; 95: 154-161
        • Ratajczak P.
        • Damy T.
        • Heymes C.
        • et al.
        Caveolin-1 and -3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat.
        Cardiovasc Res. 2003; 57: 358-369
        • Cho W.
        • Chow A.K.
        • Schulz R.
        • Daniel E.E.
        Caveolin-1 exists and may function in cardiomyocyte.
        Can J Physiol Pharmacol. 2010; 88: 73-76
        • Zhao Y.
        • Liu Y.
        • Stan R.V.
        • et al.
        Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice.
        Proc Natl Acad Sci USA. 2002; 99: 11375-11380
        • Patel H.
        • Tsutsumi Y.M.
        • Head B.P.
        • et al.
        Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin-1.
        FASEB J. 2007; 21: 1565-1574
        • Greener I.
        • Sasano T.
        • Wan X.
        • et al.
        Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction.
        J Am Coll Cardiol. 2012; 60: 1103-1110
        • van Rijen H.V.
        • Eckardt D.
        • Degen J.
        • et al.
        Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43.
        Circulation. 2004; 109: 1048-1055
        • Schilling J.
        • Horikawa Y.T.
        • Zemljic-Harpf A.E.
        • et al.
        Electrophysiology and metabolism of caveolin-3-overexpressing mice.
        Basic Res Cardiol. 2016; 111: 28
        • Kong P.
        • Christia P.
        • Frangogiannis N.G.
        The pathogenesis of cardiac fibrosis.
        Cell Mol Life Sci. 2014; 71: 549-574
        • Khalil H.
        • Kanisicak O.
        • Prasad V.
        • et al.
        Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis.
        J Clin Invest. 2017; 127: 3770-3783
        • Darby P.
        • Kwan C.Y.
        • Daniel E.E.
        Caveolae from canine airway smooth muscle contain the necessary components for a role in Ca(2+) handling.
        Am J Physiol Lung Cell Mol Physiol. 2000; 279: L1226-L1235
        • Ikeda Y.
        • Hoshijima M.
        • Chien K.R.
        Toward biologically targeted therapy of calcium cycling defects in heart failure.
        Physiology (Bethesda). 2008; 23: 6-16
        • Fauconnier J.
        • Thireau J.
        • Reiken S.
        • et al.
        Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.
        Proc Natl Acad Sci. 2010; 107: 1559-1564
        • Sipido K.
        • Volders P.G.
        • Vos M.A.
        • Verdonck F.
        Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy?.
        Cardiovasc Res. 2002; 53: 782-805
        • Pei J.
        • Yu X.C.
        • Fung M.L.
        • et al.
        Impaired G(s)alpha and adenylyl cyclase cause beta-adrenoceptor desensitization in chronically hypoxic rat hearts.
        Am J Physiol Cell Physiol. 2000; 279: C1455-C1463
        • Baker D.
        • Hashimoto K.
        • Grupp I.L.
        • et al.
        Targeted overexpression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts.
        Circ Res. 1998; 83: 1205-1214
        • Shigekawa M.
        • Iwamoto T.
        Cardiac Na(+)-Ca(2+) exchange: molecular and pharmacological aspects.
        Circ Res. 2001; 88: 864-876
        • Quinn F.
        • Currie S.
        • Duncan A.M.
        • et al.
        Myocardial infarction causes increased expression but decreased activity of the myocardial Na+-Ca2+ exchanger in the rabbit.
        J Physiol. 2003; 553: 229-242