Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. Circ Arrhythm Electrophysiol 2014 Aug;7(4):701-10
Date
07/16/2014Pubmed ID
25017399Pubmed Central ID
PMC4198950DOI
10.1161/CIRCEP.113.001394Scopus ID
2-s2.0-84907876417 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
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.
METHODS AND 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.
Author List
Yang KC, Rutledge CA, Mao M, Bakhshi FR, Xie A, Liu H, Bonini MG, Patel HH, Minshall RD, Dudley SC JrMESH terms used to index this publication - Major topics in bold
AnimalsArrhythmias, Cardiac
Caveolin 1
Connexin 43
Disease Models, Animal
Enzyme Activation
Gap Junctions
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mitochondria, Heart
Myocytes, Cardiac
Nitric Oxide Synthase Type III
Nitrosation
Peptidyl-Dipeptidase A
Protein Kinase Inhibitors
Protein Processing, Post-Translational
Reactive Oxygen Species
Renin-Angiotensin System
Signal Transduction
src-Family Kinases
