title: Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase.
abstract: BACKGROUND
  Genome-wide association studies have revealed significant association of caveolin-1 (Cav1) gene variants with increased risk of cardiac arrhythmias. Nevertheless, the mechanism for this linkage is unclear.
  
  
  RESULTS
  Using adult Cav1(-/-) mice, we revealed a marked reduction in the left ventricular conduction velocity in the absence of myocardial Cav1, which is accompanied with increased inducibility of ventricular arrhythmias. Further studies demonstrated that loss of Cav1 leads to the activation of cSrc tyrosine kinase, resulting in the downregulation of connexin 43 and subsequent electric abnormalities. Pharmacological inhibition of cSrc mitigates connexin 43 downregulation, slowed conduction, and arrhythmia inducibility in Cav1(-/-) animals. Using a transgenic mouse model with cardiac-specific overexpression of angiotensin-converting enzyme (ACE8/8), we demonstrated that, on enhanced cardiac renin-angiotensin system activity, Cav1 dissociated from cSrc because of increased Cav1 S-nitrosation at Cys(156), leading to cSrc activation, connexin 43 reduction, impaired gap junction function, and subsequent increase in the propensity for ventricular arrhythmias and sudden cardiac death. Renin-angiotensin system-induced Cav1 S-nitrosation was associated with increased Cav1-endothelial nitric oxide synthase binding in response to increased mitochondrial reactive oxidative species generation.
  
  
  CONCLUSIONS
  The present studies reveal the critical role of Cav1 in modulating cSrc activation, gap junction remodeling, and ventricular arrhythmias. These data provide a mechanistic explanation for the observed genetic link between Cav1 and cardiac arrhythmias in humans and suggest that targeted regulation of Cav1 may reduce arrhythmic risk in cardiac diseases associated with renin-angiotensin system activation.
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Kai-Chien
authors.initials: KC
authors.lastname: Yang
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Cody A
authors.initials: CA
authors.lastname: Rutledge
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Farnaz R
authors.initials: FR
authors.lastname: Bakhshi
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: An
authors.initials: A
authors.lastname: Xie
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.).
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: From the Lifespan Cardiovascular Research Center, Department of Medicine, Warren Alpert School of Medicine, Brown University, Providence Veterans Administration Medical Center, RI (K.-C.Y., C.A.R., A.X., H.L., S.C.D.); Department of Medicine (K.-C.Y., C.A.R.), Department of Pharmacology (M.M., M.G.B., R.D.M.), and Department of Anesthesiology (F.R.B., R.D.M.), University of Illinois at Chicago; and Department of Anesthesiology, VA San Diego Healthcare Systems, University of California (H.H.P.). samuel_dudley@brown.edu.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000081247:CSK Tyrosine-Protein Kinase; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D017629:Gap Junctions / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015538:Nitrosation; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D018031:Connexin 43; C543076:GJA1 protein, mouse; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D007703:Peptidyl-Dipeptidase A
keywords: arrhythmias, cardiac; caveolin 1; connexin 43; renin–angiotensin system