Inhibition of glycogen synthase kinase 3beta during heart failure is protective

• Published in: Circulation research 2007-11, Vol.101 (11), p.1164-1174
• Main Authors: Hirotani, Shinichi, Zhai, Peiyong, Tomita, Hideharu, Galeotti, Jonathan, Marquez, Juan Pablo, Gao, Shumin, Hong, Chull, Yatani, Atsuko, Avila, Jesús, Sadoshima, Junichi
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cardiomegaly - etiology; Cardiotonic Agents; Down-Regulation; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fibrosis - etiology; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta; Heart Failure - drug therapy; Mice; Mice, Transgenic; Myeloid Cell Leukemia Sequence 1 Protein; Myocardial Contraction; Neoplasm Proteins - physiology; Proto-Oncogene Proteins c-bcl-2 - physiology
• ISSN: 1524-4571

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