Cardiac-Specific Overexpression of Caveolin-3 Attenuates Cardiac Hypertrophy and Increases Natriuretic Peptide Expression and Signaling

Introduction Natriuretic peptides modulate cardiac hypertrophy and are potential therapeutic options for patients with heart failure. Caveolae, microdomains in the plasma membrane that contain caveolin proteins and natriuretic peptide receptors, have been implicated in cardiac hypertrophy and natriuretic peptide localization. We hypothesized that cardiac myocyte-specific overexpression of caveolin-3, a muscle-specific caveolin, would alter natriuretic peptide signaling and attenuate cardiac hypertrophy. Methods and Results We generated transgenic mice with cardiac myocyte-specific overexpression of caveolin-3 (Cav-3 OE) and also used an adenoviral construct to increase Cav-3 in cardiac myocytes. Cav-3 OE mice subjected to transverse aortic constriction had increased survival, reduced cardiac hypertrophy and maintenance of cardiac function compared to control mice. In left ventricle at baseline, mRNA for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were increased 7-fold and 3-fold, respectively in Cav-3 OE mice compared to controls and were accompanied by increased protein expression for ANP and BNP. In addition, ventricles from Cav-3 OE mice had greater cGMP levels, less NFAT nuclear translocation, and more nuclear Akt phosphorylation than did ventricles from controls. Cardiac myocytes incubated with Cav-3 adenovirus showed increased expression of Cav-3, ANP, and Akt phosphorylation. Incubation with methyl-β-cyclodextrin, which disrupts caveolae, or with wortmannin, a PI3K inhibitor, blocked the increase in ANP expression. Discussion These results imply that cardiac myocyte-specific overexpression of Cav-3 is a novel strategy to enhance natriuretic peptide expression, attenuate hypertrophy and possibly exploit the therapeutic benefits of natriuretic peptides in cardiac hypertrophy and heart failure.