Inhibition of Glycogen Synthase Kinase 3 During Heart Failure Is Protective

Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3 in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3 (Tg-GSK-3 -DN) and tetracycline-regulatable wild-type GSK-3 . GSK-3 -DN significantly reduced the kinase activity of endogenous GSK-3 , inhibited phosphorylation of eukaryotic translation initiation factor 2B , and induced accumulation of -catenin and myeloid cell leukemia-1, confirming that GSK-3 -DN acts as a dominant negative in vivo. Tg-GSK-3 -DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the -myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater Emax after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3 induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3 -DN and nontransgenic mice, Tg-GSK-3 -DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3 transgene in tetracycline-regulatable wild-type GSK-3 mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3 -DN in cardiac myocytes inhibited tumor necrosis factor–induced apoptosis, and the antiapoptotic effect of GSK-3 -DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3 induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3 inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3 during heart failure could be compensatory. (Circ Res. 2007;101:1164-1174.)