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J. Biol. Chem., Vol. 279, Issue 6, 4782-4793, February 6, 2004

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The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110) Pathway^*

Julie R. McMullen¶, Tetsuo Shioi||, Weei-Yuarn Huang, Li Zhang, Oleg Tarnavski, Egbert Bisping, Martina Schinke, Sekwon Kong, Megan C. Sherwood**, Jeffrey Brown, Lauren Riggi, Peter M. Kang, and Seigo Izumo

From the Beth Israel Deaconess Medical Center, Harvard Medical School, and the ^**Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02215

Insulin-like growth factor 1 (IGF1) was considered a potential candidate for the treatment of heart failure. However, some animal studies and clinical trials have questioned whether elevating IGF1 chronically is beneficial. Secondary effects of increased serum IGF1 levels on other tissues may explain these unfavorable results. The aim of the current study was to examine the role of IGF1 in cardiac myocytes in the absence of secondary effects, and to elucidate downstream signaling pathways and transcriptional regulatory effects of the IGF1 receptor (IGF1R). Transgenic mice overexpressing IGF1R in the heart displayed cardiac hypertrophy, which was the result of an increase in myocyte size, and there was no evidence of histopathology. IGF1R transgenics also displayed enhanced systolic function at 3 months of age, and this was maintained at 12-16 months of age. The phosphoinositide 3-kinase (PI3K)-Akt-p70S6K1 pathway was significantly activated in hearts from IGF1R transgenics. Cardiac hypertrophy induced by overexpression of IGF1R was completely blocked by a dominant negative PI3K(p110) mutant, suggesting IGF1R promotes compensated cardiac hypertrophy in a PI3K(p110)-dependent manner. This study suggests that targeting the cardiac IGF1R-PI3K(p110) pathway could be a potential therapeutic strategy for the treatment of heart failure.

Received for publication, September 22, 2003 , and in revised form, October 27, 2003.

^* This work was supported by National Institutes of Health Grant RO1 HL65742 and by Grant UO1-HL66582 (to S. I.) from the CardioGenomics Program for Genomic Applications, NHLBI, National Institutes of Health. 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 additional microarray data.

Both authors contributed equally to this work.

^|| Present address: Dept. of Internal Medicine and Cardiology, Kitasato University, School of Medicine, Sagamihara 228-8555, Japan.

^¶ To whom correspondence should be addressed: Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Tel.: 617-667-4863; Fax: 617-975-5268; E-mail: jmcmulle{at}bidmc.harvard.edu.

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