Akt2: A Critical Regulator of Cardiomyocyte Survival and Metabolism

Akt proteins are serine/threonine protein kinases that participate in several important intracellular signal transduction cascades. Akt1 and Akt2 are expressed in cardiomyocytes, and both are activated by the action of a variety of growth factors and extracellular ligands. In work with genetically modified mice that had targeted disruption of the genes encoding Akt1 or Akt2, findings showed that Akt1 specifically regulated the physiologic growth of cardiomyocytes that occurred in response to exercise training. In contrast, Akt2 does not regulate physiologic growth but instead regulates glucose metabolism in response to insulin stimulation in cardiomyocytes. Furthermore, Akt2 plays a critical role in antagonizing cardiomyocyte apoptosis that occurs in response to a variety of stimuli, including pathologic remodeling after experimental myocardial infarction. In addition, the protein tribbles 3 (TRB3), an Akt antagonist, was found to be expressed in cardiomyocytes and to be induced by stimuli that cause endoplasmic reticulum stress. Endoplasmic reticulum stress-mediated antagonism of Akt signaling in cardiomyocytes was dependent on TRB3 induction. Finally, myocardial infarction caused endoplasmic reticulum stress in the infarct border zone that was associated with TRB3 induction. These results demonstrate the differential roles of Akt family members and the importance of Akt2 in cardiomyocyte survival.