on April 24, 2006
Circulation. 2006
Published online before print April 24, 2006, doi: 10.1161/CIRCULATIONAHA.105.595231
Published online before print April 24, 2006, doi: 10.1161/CIRCULATIONAHA.105.595231
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Submitted on October 13, 2005
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. * To whom correspondence should be addressed. E-mail: amuslin{at}imgate.wustl.edu.
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.
Revised on February 13, 2006
Accepted on February 17, 2006
Akt1 Is Required for Physiological Cardiac Growth
Brian DeBosch BS,
Key words: heart failure • hypertrophy • signal transduction
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