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(Circulation. 2006;113:2097-2104.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Akt1 Is Required for Physiological Cardiac Growth

Brian DeBosch, BS; Iya Treskov, BS; Traian S. Lupu, DVM; Carla Weinheimer, MS; Attila Kovacs, MD; Michael Courtois, MA; Anthony J. Muslin, MD

From the Center for Cardiovascular Research, Department of Medicine (B.D., I.T., T.S.L., C.W., A.K., M.C., A.J.M.), and Department of Cell Biology and Physiology (B.D., I.T., T.S.L., A.J.M.), Washington University School of Medicine, St Louis, Mo.

Correspondence to Anthony J. Muslin, Center for Cardiovascular Research, Box 8086, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110. E-mail amuslin{at}imgate.wustl.edu

Received October 13, 2005; revision received February 13, 2006; accepted February 17, 2006.

Background— Postnatal growth of the heart chiefly involves nonproliferative cardiomyocyte enlargement. Cardiac hypertrophy exists in a "physiological" form that is an adaptive response to long-term exercise training and as a "pathological" form that often is a maladaptive response to provocative stimuli such as hypertension and aortic valvular stenosis. A signaling cascade that includes the protein kinase Akt regulates the growth and survival of many cell types, but the precise role of Akt1 in either form of cardiac hypertrophy is unknown.

Methods and Results— To evaluate the role of Akt1 in physiological cardiac growth, akt1^–/– adult murine cardiac myocytes (AMCMs) were treated with IGF-1, and akt1^–/– mice were subjected to exercise training. akt1^–/– AMCMs were resistant to insulin-like growth factor-1–stimulated protein synthesis. The akt1^–/– mice were found to be resistant to swimming training–induced cardiac hypertrophy. To evaluate the role of Akt in pathological cardiac growth, akt1^–/– AMCMs were treated with endothelin-1, and akt1^–/– mice were subjected to pressure overload by transverse aortic constriction. Surprisingly, akt1^–/– AMCMs were sensitized to endothelin-1–induced protein synthesis, and akt1^–/– mice developed an exacerbated form of cardiac hypertrophy in response to transverse aortic constriction.

Conclusions— These results establish Akt1 as a pivotal regulatory switch that promotes physiological cardiac hypertrophy while antagonizing pathological hypertrophy.

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