Cardiac-Specific Overexpression of Caveolin-3 Induces Endogenous Cardiac Protection by Mimicking Ischemic Preconditioning

• Published in: Circulation (New York, N.Y.) N.Y.), 2008-11, Vol.118 (19), p.1979-1988
• Main Authors: TSUTSUMI, Yasuo M, HORIKAWA, Yousuke T, PATEL, Piyush M, INSEL, Paul A, PATEL, Hemal H, ROTH, David M, JENNINGS, Michelle M, KIDD, Michael W, NIESMAN, Ingrid R, YOKOYAMA, Utako, HEAD, Brian P, HAGIWARA, Yasuko, ISHIKAWA, Yoshihiro, MIYANOHARA, Atsushi
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Apoptosis - physiology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Caveolae - physiology; Caveolae - ultrastructure; Caveolin 3 - genetics; Caveolin 3 - metabolism; Cholesterol - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Gene Expression - physiology; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Ischemic Preconditioning, Myocardial; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Myocytes, Cardiac - pathology; Myocytes, Cardiac - physiology; Myocytes, Cardiac - ultrastructure; Nitric Oxide Synthase - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Sarcolemma - physiology; Sarcolemma - ultrastructure
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.108.788331

Caveolae, lipid-rich microdomains of the sarcolemma, localize and enrich cardiac-protective signaling molecules. Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of caveolar formation. We hypothesized that cardiac myocyte-specific overexpression of Cav-3 would enhance the formation of caveolae and augment cardiac protection in vivo. Ischemic preconditioning in vivo increased the formation of caveolae. Adenovirus for Cav-3 increased caveolar formation and phosphorylation of survival kinases in cardiac myocytes. A transgenic mouse with cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) showed enhanced formation of caveolae on the sarcolemma. Cav-3 OE mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to transgene-negative mice. Endogenous cardiac protection in Cav-3 OE mice was similar to wild-type mice undergoing ischemic preconditioning; no increased protection was observed in preconditioned Cav-3 OE mice. Cav-3 knockout mice did not show endogenous protection and showed no protection in response to ischemic preconditioning. Cav-3 OE mouse hearts had increased basal Akt and glycogen synthase kinase-3beta phosphorylation comparable to wild-type mice exposed to ischemic preconditioning. Wortmannin, a phosphoinositide 3-kinase inhibitor, attenuated basal phosphorylation of Akt and glycogen synthase kinase-3beta and blocked cardiac protection in Cav-3 OE mice. Cav-3 OE mice had improved functional recovery and reduced apoptosis at 24 hours of reperfusion. Expression of caveolin-3 is both necessary and sufficient for cardiac protection, a conclusion that unites long-standing ultrastructural and molecular observations in the ischemic heart. The present results indicate that increased expression of caveolins, apparently via actions that depend on phosphoinositide 3-kinase, has the potential to protect hearts exposed to ischemia/reperfusion injury.