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-3β in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3β (Tg-GSK-3β-DN) and tetracycline-regulatable wild-type GSK-3β. GSK-3β-DN significantly reduced the kinase activity of endogenous GSK-3β, inhibited phosphorylation of eukaryotic translation initiation factor 2Bε, and induced accumulation of β-catenin and myeloid cell leukemia-1, confirming that GSK-3β-DN acts as a dominant negative in vivo. Tg-GSK-3β-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the α-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-3β induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3β-DN and nontransgenic mice, Tg-GSK-3β-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3β transgene in tetracycline-regulatable wild-type GSK-3β mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3β-DN in cardiac myocytes inhibited tumor necrosis factor-α–induced apoptosis, and the antiapoptotic effect of GSK-3β-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3β induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3β inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3β during heart failure could be compensatory.Supported by United States Public Health Service grants HL 59139, HL67724, HL69020, AG23039, and AG28787; and American Heart Association Grant 0340123N. S.H. and H.T. were supported by Postdoctoral Fellowships from the American Heart Association Heritage Affiliate.Peer reviewe