Abstract 412: Cardiac-Specific Overexpression of Caveolin-3 Induces Endogenous Cardiac Protection
Caveolae are lipid-rich microdomains of the plasma membrane that localize and enrich cardiac protective signaling molecules. Caveolin-3 (Cav3), the dominant caveolin isoform found in cardiac myocytes, is a determinant of caveolae formation. We hypothesized that cardiac-directed overexpression of Cav3 would enhance the formation of caveolae and augment protective signaling of the heart in vivo. Full-length cDNA for 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 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. Tg-positive mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to Tg-negative mice (23.9 ± 3.3 vs. 44.4 ± 5.9 % risk area, p<0.01). The endogenous protection induced in Cav-3 Tg-positive mice was similar to that produced in wild-type mice undergoing ischemic preconditioning (27.2 ± 2.5 % risk area). 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). Cardiac protection in Cav3 Tg-positive mice was blocked by treatment prior to ischemia reperfusion with 5-hydroxydecanoate, a mitochondrial KATP channel blocker. These results reveal that cardiac-specific overexpression of Cav3 produces an endogenous protected phenotype in mice in association with greater basal Akt activation and a phenotype that is sensitive to antagonism via mitochondrial KATP channel inhibition. The findings suggest that approaches to increase Cav3 expression may provide a novel means to augment cardiac protection independent of ischemic preconditioning.