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

Background: Ischemic cardiomyopathy (ICM) is associated with elec-trical 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 arrhyth-mogenicity. The current study aimed to determine how Cav1 over -expression inhibits arrhythmias and cardiac remodelling in ICM. Methods: ICM was modelled using left anterior descending (LAD) ar-tery ligation for 4 weeks. Cardiac-specific Cav1 overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodel-ling were investigated using the intramyocardial injection of an adeno-associated virus serotype 9 (AAV-9) system, carrying a specific sequence expressing Cav1 (AAVCav1) under the cardiac troponin T (cTnT) promoter.Results: Cav1 overexpression decreased susceptibility to arrhythmias by upregulating gap junction connexin 43 (CX43) and reducing spon-taneous irregular proarrhythmogenic Ca2 +/- waves in ventricular car-diomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca2 +/- cycling through normalizing Ca2 +/-- handling protein levels and improving Ca2 +/- homeostasis. Masson stain and immunoblotting revealed that the deposition of excessive fibrosis was attenuated by Cav1 overexpression, inhibiting the transforming growth factor -(3 (TGF-(3)/Smad2 signalling pathway. Coimmunopreci-pitation assays demonstrated that the interaction between Cav1 and cSrc modulated CX43 expression and Ca2 +/--handling protein levels.Conclusions: Cardiac-specific overexpression of Cav1 attenuated ventricular arrhythmia, improved Ca2 +/- cycling, and attenuated cardiac remodelling. These effects were attributed to modulation of CX43, normalized Ca2 +/--handling protein levels, improved Ca2 +/- homeostasis, and attenuated cardiac fibrosis.