Published online before print February 26, 2004, doi: 10.1161/01.RES.0000124394.01180.BE
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Submitted on September 18, 2003
Revised on February 3, 2004
Accepted on February 17, 2004
Nuclear Targeting of Akt Enhances Kinase Activity and Survival of Cardiomyocytes
Isao Shiraishi ;
From The Children’s Hospital Research Foundation (I.S., J.M., S.W.), Division of Molecular Cardiovascular Biology; Cincinnati, Ohio; Massachusetts General Hospital (Y.A., A.R.), Harvard Medical School, Charlestown, Mass; National Institute of Environmental Health Sciences, Laboratory of Signal Transduction (M.S., E.M.), Research Triangle Park, NC; Biosource International (E.S.), Hopkinton, Mass; Boston University School of Medicine (K.W.), Whitaker Cardiovascular/Molecular Cardiology, Boston, Mass; Cardiovascular Research Institute (D.T., D.N., J.K., A.L., P.A.), New York Medical College, Valhalla, NY; and SDSU Heart Institute and Department of Biology (M.A.S.), San Diego State University, San Diego, Calif.
* To whom correspondence should be addressed. E-mail: sussman{at}sciences.sdsu.edu.
Heart failure is associated with death of cardiomyocytes leading to loss of contractility. Previous studies using membrane-targeted Akt (myristolated-Akt), an enzyme involved in antiapoptotic signaling, showed inhibition of cell death and prevention of pathogenesis induced by cardiomyopathic stimuli. However, recent studies by our group have found accumulation of activated Akt in the nucleus, suggesting that biologically relevant target(s) of Akt activity may be located there. To test this hypothesis, a targeted Akt construct was created to determine the antiapoptotic action of nuclear Akt accumulation. Nuclear localization of the adenovirally encoded Akt construct was confirmed by confocal microscopy. Cardiomyocytes expressing nuclear-targeted Akt showed no evidence of morphological remodeling such as altered myofibril density or hypertrophy. Nuclear-targeted Akt significantly elevated levels of phospho-Akt and kinase activity and inhibited apoptosis as effectively as myristolated-Akt in hypoxia-induced cell death. Transgenic overexpression of nuclear-targeted Akt did not result in hypertrophic remodeling, altered cardiomyocyte DNA content or nucleation, or enhanced phosphorylation of typical cytoplasmic Akt substrates, yet transgenic hearts were protected from ischemia-reperfusion injury. Gene array analyses demonstrated changes in the transcriptional profile of Akt/nuc hearts compared with nontransgenic controls distinct from prior characterizations of Akt expression in transgenic hearts. Collectively, these experiments show that targeting of Akt to the nucleus mediates inhibition of apoptosis without hypertrophic remodeling, opening new possibilities for therapeutic applications of nuclear-targeted Akt to inhibit cell death associated with heart disease.
Key words: Akt • apoptosis • nuclear • cardiomyocytes • transgenic
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