Cardiac‐Specific Overexpression of Caveolin‐3 Enhances Akt Phosphorylation

Abstract

Caveolin-3 (Cav3), a membrane protein that helps define lipid raft/caveolar domains, is a potent activator of PI3-K/Akt signaling, an important pathway in cardiac protection. We hypothesized that cardiac-directed overexpression of Cav3 augments PI3-K/Akt cardiac protective signaling in vivo. Mouse Cav3 was cloned into a vector containing the α-myosin heavy chain promoter to allow for cardiac myocyte-specific expression of Cav3. A transgenic (Tg) mouse line was derived with a 5.5-fold increase in Cav3 mRNA and a 2.4-fold increase in Cav3 protein that localized specifically to the sarcolemma. No significant increase in Cav3 expression was observed in lung, liver, brain, or skeletal muscle from Tg-positive mice. Electron microscopy revealed enhanced formation of caveolae on the sarcolemmal membranes of Tg-positive mice compared to Tg-negative littermate controls and no apparent structural defects in the heart. Echocardiography of 7–9 month old Tg-positive and Tg-negative mice showed no significant differences in cardiac function. Hearts excised from Tg-positive mice had a 1.5-fold increase in basal phosphorylation of Akt (p<0.05, n=6 TG positive, 4 Tg-negative). Treatment with isoflurane (30 min, 1.4%), an agent that produces cardiac protection and activates Akt signaling, produced a 2.5-fold greater increase in phosphorylation of Akt in Tg-positive vs. Tg-negative animals (n=3/group). These results reveal that cardiac-specific overexpression of Cav3 produces a phenotype in mice with greater basal and stimulated PI3-K/Akt signaling, thus suggesting that approaches to increase Cav3 expression may provide a novel means to augment cardiac protection and perhaps other effects mediated by PI3-K/Akt.