(Circulation. 2001;104:330.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Akt Activation Preserves Cardiac Function and Prevents Injury After Transient Cardiac Ischemia In Vivo
From the Program in Cardiovascular Gene Therapy, CVRC (T.M., J.T., F.d.M., K.-H.L., L.L., R.J.H., A.R.), and Cardiology Division (M.P., T.L.F., R.J.H., A.R.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; the Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (K.-H.L.); and the Department of Pharmacology, Columbia University, New York, NY (T.F.F.).
Correspondence to Anthony Rosenzweig, MD, Massachusetts General Hospital, 149 13th St, Room 4214, Charlestown, MA 02129. E-mail rosenzweig{at}helix.mgh.harvard.edu
Background— The serine-threonine kinase Akt is activated by several ligand-receptor systems previously shown to be cardioprotective. Akt activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role in cardiac dysfunction or infarction, however, remains unclear.
Methods and Results— We examined the effects of a constitutively active Akt mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. In vivo gene transfer of myr-Akt reduced infarct size by 64% and the number of apoptotic cells by 84% (P<0.005 for each). Ischemia-reperfusion injury decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise and fall (+dP/dt and -dP/dt). Akt activation restored regional wall thickening and +dP/dt and -dP/dt to levels seen in sham-operated rats. To better understand this benefit, we examined the effects of myr-Akt on hypoxic cardiomyocyte dysfunction in vitro. myr-Akt prevented hypoxia-induced abnormalities in cardiomyocyte calcium transients and shortening. Akt activation also enhanced sarcolemmal expression of Glut-4 in vivo and increased glucose uptake in vitro to the level seen with insulin treatment.
Conclusions— Akt activation exerts a powerful cardioprotective effect after transient ischemia that probably reflects its ability to both inhibit cardiomyocyte death and improve function of surviving cardiomyocytes. Akt may represent an important nodal target for therapy in ischemic and other heart disease.
Key Words: apoptosis • signal transduction • gene therapy • ischemia
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