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J. Biol. Chem., Vol. 281, Issue 43, 32841-32851, October 27, 2006

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Akt2 Regulates Cardiac Metabolism and Cardiomyocyte Survival^*

Brian DeBosch¹, Nandakumar Sambandam, Carla Weinheimer, Michael Courtois, and Anthony J. Muslin²

From the Center for Cardiovascular Research, Department of Medicine and the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

The Akt family of serine-threonine kinases participates in diverse cellular processes, including the promotion of cell survival, glucose metabolism, and cellular protein synthesis. All three known Akt family members, Akt1, Akt2 and Akt3, are expressed in the myocardium, although Akt1 and Akt2 are most abundant. Previous studies demonstrated that Akt1 and Akt3 overexpression results in enhanced myocardial size and function. Yet, little is known about the role of Akt2 in modulating cardiac metabolism, survival, and growth. Here, we utilize murine models with targeted disruption of the akt2 or the akt1 genes to demonstrate that Akt2, but not Akt1, is required for insulin-stimulated 2-[³H]deoxyglucose uptake and metabolism. In contrast, akt2^-/- mice displayed normal cardiac growth responses to provocative stimulation, including ligand stimulation of cultured cardiomyocytes, pressure overload by transverse aortic constriction, and myocardial infarction. However, akt2^-/- mice were found to be sensitized to cardiomyocyte apoptosis in response to ischemic injury, and apoptosis was significantly increased in the peri-infarct zone of akt2^-/- hearts 7 days after occlusion of the left coronary artery. These results implicate Akt2 in the regulation of cardiomyocyte metabolism and survival.

Received for publication, December 8, 2005 , and in revised form, August 21, 2006.

^* This work was supported in part by National Institutes of Health (NIH) Grants HL61567, HL057278, and HL076670, by the Burroughs Wellcome Fund (to A. J. M.), and by the Washington University Digestive Diseases Research Core Center (NIH Grant P30 DK52574). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S7.

¹ Supported by Cardiovascular Physiology Training Grant T32-HL07873.

² To whom correspondence should be addressed: Center for Cardiovascular Research, Dept. of Medicine, Washington University School of Medicine, 4940 Parkview Place, Box 8086, Rm. 9912 CSRB, St. Louis, MO 63110. Tel.: 314-747-3525; Fax: 314-747-3545; E-mail: amuslin{at}im.wustl.edu.

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