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