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J. Biol. Chem., Vol. 283, Issue 39, 26484-26489, September 26, 2008

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Transgenic Overexpression of Hdac3 in the Heart Produces Increased Postnatal Cardiac Myocyte Proliferation but Does Not Induce Hypertrophy^*

Chinmay M. Trivedi¹, Min Min Lu, Qiaohong Wang, and Jonathan A. Epstein, Holds the W. W. Smith Endowed Chair for Cardiovascular Research at the University of Pennsylvania²

From the Department of Cell and Developmental Biology and the Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Class I and II histone deacetylases (HDACs) play vital roles in regulating cardiac development, morphogenesis, and hypertrophic responses. Although the roles of Hdac1 and Hdac2, class I HDACs, in cardiac hyperplasia, growth, and hypertrophic responsiveness have been reported, the role in the heart of Hdac3, another class I HDAC, has been less well explored. Here we report that myocyte-specific overexpression of Hdac3 in mice results in cardiac abnormalities at birth. Hdac3 overexpression produces thickening of ventricular myocardium, especially the interventricular septum, and reduction of both ventricular cavities in newborn hearts. Our data suggest that increased thickness of myocardium in Hdac3-transgenic (Hdac3-Tg) mice is due to increased cardiomyocyte hyperplasia without hypertrophy. Hdac3 overexpression inhibits several cyclin-dependent kinase inhibitors, including Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, and Cdkn2c. Hdac3-Tg mice did not develop cardiac hypertrophy at 3 months of age, unlike previously reported Hdac2-Tg mice. Further, Hdac3 overexpression did not augment isoproterenol-induced cardiac hypertrophy when compared with wild-type littermates. These findings identify Hdac3 as a novel regulator of cardiac myocyte proliferation during cardiac development.

Received for publication, May 13, 2008 , and in revised form, July 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 HL071546 (to J. A. E.). 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.

¹ Supported by an American Heart Association postdoctoral fellowship (0625427U).

² To whom correspondence should be addressed: 1154 BRB II, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-8731; Fax: 215-898-9871; E-mail: epsteinj{at}mail.med.upenn.edu.

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