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J. Biol. Chem., Vol. 282, Issue 45, 33181-33191, November 9, 2007

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Glycogen Synthase Kinase-3 Reduces Cardiac Growth and Pressure Overload-induced Cardiac Hypertrophy by Inhibition of Extracellular Signal-regulated Kinases^*

Peiyong Zhai¹, Shumin Gao, Eric Holle, Xianzhong Yu, Atsuko Yatani, Thomas Wagner, and Junichi Sadoshima²

From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103 and Oncology Research Institute, Greenville, South Carolina 29605

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase having multiple functions and consisting of two isoforms, GSK-3 and GSK-3. Pressure overload increases expression of GSK-3 but not GSK-3. Despite our wealth of knowledge about GSK-3, the function of GSK-3 in the heart is not well understood. To address this issue, we made cardiac-specific GSK-3 transgenic mice (Tg). Left ventricular weight and cardiac myocyte size were significantly smaller in Tg than in non-Tg (NTg) mice, indicating that GSK-3 inhibits cardiac growth. After 4 weeks of aortic banding (transverse aortic constriction (TAC)), increases in left ventricular weight and myocyte size were significantly smaller in Tg than in NTg, indicating that GSK-3 inhibits cardiac hypertrophy. More severe cardiac dysfunction developed in Tg after TAC. Increases in fibrosis and apoptosis were greater in Tg than in NTg after TAC. Among signaling molecules screened, ERK phosphorylation was decreased in Tg. Adenovirus-mediated overexpression of GSK-3, but not GSK-3, inhibited ERK in cultured cardiac myocytes. Knockdown of GSK-3 increased ERK phosphorylation, an effect that was inhibited by PD98059, rottlerin, and protein kinase C (PKC) inhibitor peptide, suggesting that GSK-3 inhibits ERK through PKC-MEK-dependent mechanisms. Knockdown of GSK-3 increased protein content and reduced apoptosis, effects that were abolished by PD98059, indicating that inhibition of ERK plays a major role in the modulation of cardiac growth and apoptosis by GSK-3. In conclusion, up-regulation of GSK-3 inhibits cardiac growth and pressure overload-induced cardiac hypertrophy but increases fibrosis and apoptosis in the heart. The anti-hypertrophic and pro-apoptotic effect of GSK-3 is mediated through inhibition of ERK.

Received for publication, June 21, 2007 , and in revised form, August 21, 2007.

^* This work was supported by National Institutes of Health Grants HL33107, HL59139, HL67724, HL67727, HL69020, and HL73048 and by American Heart Association Grant 0340123N. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. I-V.

¹ Supported by National Institutes of Health Grant 1 F32 HL080861.

² To whom correspondence should be addressed: 185 South Orange Ave., MSB G609, Newark, NJ 07103. Tel.: 973-972-8619; Fax: 973-972-8919; E-mail: sadoshju{at}umdnj.edu.

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