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(Circulation. 2008;118:1979-1988.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

Yasuo M. Tsutsumi, MD, PhD; Yousuke T. Horikawa, BS; Michelle M. Jennings, BS; Michael W. Kidd, BS; Ingrid R. Niesman, MS; Utako Yokoyama, MD, PhD; Brian P. Head, PhD; Yasuko Hagiwara, PhD; Yoshihiro Ishikawa, MD, PhD; Atsushi Miyanohara, PhD; Piyush M. Patel, MD; Paul A. Insel, MD; Hemal H. Patel, PhD^*; David M. Roth, MD, PhD^*

From the Departments of Anesthesiology (Y.M.T., Y.T.H., M.M.J., M.W.K., I.R.N., B.P.H., P.M.P., H.H.P., D.M.R.), Pharmacology (U.Y., P.A.I.), and Medicine (P.A.I.) and Gene Therapy Program (A.M.), University of California, San Diego, La Jolla; National Institute of Neuroscience, Kodaira, Tokyo, Japan (Y.H.); Cardiovascular Research Institute, Yokohama City University School of Medicine, Yokohama, Kanazawa, Japan (Y.I.); Department of Cell Biology and Molecular Medicine (Y.I.) and Department of Medicine (Cardiology Division) (Y.I.), New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark; and Department of Anesthesiology, VA San Diego Healthcare Systems, San Diego, Calif (P.M.P., D.M.R.).

Correspondence to Dr D.M. Roth or Dr H.H. Patel, VA San Diego Healthcare System, 9125, 3350 La Jolla Village Dr, San Diego, CA 92161–9125. E-mail droth{at}ucsd.edu or hepatel@ucsd.edu

Received April 23, 2008; accepted August 29, 2008.

Background— 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.

Methods and Results— 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-3β 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-3β 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.

Conclusions— 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.

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Circulation 2008 118: 1911-1912. [Extract] [Full Text]