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

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 (AAV) 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 Ca waves in ventricular cardiomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca cycling through normalizing Ca-handling protein levels and improving Ca 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 Ca-handling protein levels.

CONCLUSIONS

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