Published online before print September 27, 2007, doi: 10.1161/CIRCRESAHA.107.160614
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Submitted on April 9, 2007
Revised on September 12, 2007
Accepted on September 13, 2007
Inhibition of Glycogen Synthase Kinase 3
During Heart Failure Is Protective
Shinichi Hirotani ;
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 Biologi'a Molecular "Severo Ochoa" (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Autónoma de Madrid, Spain.
* To whom correspondence should be addressed. 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-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.
Key words: GSK-3
•
heart failure •
cardiac hypertrophy •
apoptosis
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