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(Circulation Research. 2007;101:1164.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Inhibition of Glycogen Synthase Kinase 3ß During Heart Failure Is Protective

Shinichi Hirotani^*, Peiyong Zhai^*, Hideharu Tomita, Jonathan Galeotti, Juan Pablo Marquez, Shumin Gao, Chull Hong, Atsuko Yatani, Jesús Avila, Junichi Sadoshima

From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biología Molecular "Severo Ochoa" (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Autónoma de Madrid, Spain.

Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular Research Institute, UMDNJ, 185 South Orange Ave, MSB G-609, Newark, NJ 07103. E-mail Sadoshju{at}umdnj.edu

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

Key Words: GSK-3ß • heart failure • cardiac hypertrophy • apoptosis

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