Abstract 9861: Caveolin 1-Regulated Src-dependent Cardiac Connexin 43 Degradation Mediates Renin-Angiotensin System Activation-Induced Arrhythmias
Background: Activation of the cardiac renin-angiotensin system (RAS) is associated with increased risk of ventricular arrhythmia and sudden cardiac death. Increased cardiac RAS activity leads to conduction block and spontaneous ventricular arrhythmias as a result of connexin 43 (Cx43) degradation mediated by the activation of redox-sensitive tyrosine kinase c-Src signaling. The molecular mechanism of c-Src activation downstream of RAS signaling remains elusive.
Results: Using a transgenic mouse model of cardiac-specific overexpression of angiotensin converting enzyme (ACE8/8) and a heterologous expression system, we uncovered a ~50% reduction in the binding of c-Src to caveolin 1 (Cav1) and subsequent c-Src activation as a result of S-nitrosylation of Cav-1 at Cys156 (Cav1-SNO) upon enhanced RAS signaling. RAS-induced Cav1-SNO and Src activation was mediated by eNOS-derived NO in response to increased mitochondrial oxidative stress. Knockout of Cav1 (but not caveolin 3) resulted in activation of c-Src, degradation of Cx43 (42% reduction from WT level), reduced cardiac conduction velocity (by 30%), and increased arrhythmic risk (75% Cav1-/- vs. 0% WT mice showed induced ventricular arrhythmia). Arrhythmic risk in Cav1-/- mice was mitigated by pharmacological inhibition of c-Src.
Conclusions: Cav1 S-nitrosylation plays a critical role in mediating RAS-induced arrhythmias by increasing c-Src activity. Oxidative stress-induced Cav1 S-nitrosylation in response to cardiac RAS signaling promotes Src-dependent disruption of Cx43 hemichannels and ventricular arrhythmia. These findings may explain the genetic association of Cav1 with arrhythmias and suggests that targeted regulation of Cav1 or antioxidant therapy may reduce arrhythmic risk during RAS activation.
- © 2013 by American Heart Association, Inc.