Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo

Background - The serine-threonine kinase Akt is activated by Several ligand -receptor systems previously shown to be cardioprotective, Akt activation r educes 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 Ak t mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. I n 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 l eft 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 s ham-operated rats. To better understand this benefit, we examined the effec ts of myr-Akt on hypoxic cardiomyocyte dysfunction in vitro, myr-Akt preven ted hypoxia-induced abnormalities in cardiomyocyte calcium transients and s hortening, 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 cardi omyocyte death and improve function of surviving cardiomyocytes, Akt may re present an important nodal target for therapy in ischemic and other heart d isease.