Cardiac-Specific Caveolin-3 Overexpression Prevents Post-Myocardial Infarction Ventricular Arrhythmias by Inhibiting Ryanodine Receptor-2 Hyperphosphorylation

Our results suggested a novel role for Cav3 in the prevention of ventricular arrhythmias, thereby identifying a new target for preventing SCD after MI.

A model of cardiac-specific overexpression of Cav3 was established to evaluate the incidence of ventricular arrhythmias after MI in mice. Ca2+ imaging was employed to detect the propensity of adult murine cardiomyocytes to generate arrhythmias, and immunoprecipitation and immunofluorescence were used to determine the relationship of proteins. Additionally, qRT-PCR and western blotting were used to detect the mRNA and protein expression.

Here, we evaluated whether caveolin-3 (Cav3), the structural protein of caveolae, plays an important role in the therapeutic strategy for ventricular arrhythmias.

We found that cardiac-specific overexpression of Cav3 delivered by a recombinant adeno-associated viral vector reduced the incidence of ventricular arrhythmias and SCD after MI in mice. Ca2+ imaging and western blotting revealed that overexpression of Cav3 reduced diastolic spontaneous Ca2+ waves by inhibiting the hyperphosphorylation of ryanodine receptor-2 (RyR2) at Ser2814, rather than at Ser2808, compared to in rAAV-red fluorescent protein control mice. Furthermore, we demonstrated that Cav3-regulated RYR2 hyperphosphorylation relied on plakophilin-2 in hypoxia-stimulated cultured cardiomyocytes by western blotting, immunoprecipitation, and immunofluorescence in vitro. Conclusions: Our results suggested a novel role for Cav3 in the prevention of ventricular arrhythmias, thereby identifying a new target for preventing SCD after MI.