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J. Biol. Chem., Vol. 281, Issue 14, 9152-9162, April 7, 2006

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Myocyte Enhancer Factors 2A and 2C Induce Dilated Cardiomyopathy in Transgenic Mice^*

Jian Xu¹, Nanling L. Gong^¶||**2, Ilona Bodi, Bruce J. Aronow, Peter H. Backx^¶||**3, and Jeffery D. Molkentin⁴

From the Departments of Pharmacology and Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, the ^¶Departments of Physiology and Medicine, the ^||Heart and Stroke Richard Lewar Centre, and the ^**Division of Cardiology, University of Toronto, Toronto, Ontario M5S 3E2, Canada, and the Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45267

Cardiac hypertrophy and dilation are mediated by neuroendocrine factors and/or mitogens as well as through internal stretch- and stress-sensitive signaling pathways, which in turn transduce alterations in cardiac gene expression through specific signaling pathways. The transcription factor family known as myocyte enhancer factor 2 (MEF2) has been implicated as a signal-responsive mediator of the cardiac transcriptional program. For example, known hypertrophic signaling pathways that utilize calcineurin, calmodulin-dependent protein kinase, and MAPKs can each affect MEF2 activity. Here we demonstrate that MEF2 transcription factors induced dilated cardiomyopathy and lengthening of myocytes. Specifically, multiple transgenic mouse lines with cardiac-specific overexpression of MEF2A or MEF2C presented with cardiomyopathy at base line or were predisposed to more fulminant disease following pressure overload stimulation. The cardiomyopathic response associated with MEF2A and MEF2C was not further altered by activated calcineurin, suggesting that MEF2 functions independently of calcineurin in this response. In cultured cardiomyocytes, MEF2A, MEF2C, and MEF2-VP16 overexpression induced sarcomeric disorganization and focal elongation. Mechanistically, MEF2A and MEF2C each programmed similar profiles of altered gene expression in the heart that included extracellular matrix remodeling, ion handling, and metabolic genes. Indeed, adenoviral transfection of cultured cardiomyocytes with MEF2A or of myocytes from the hearts of MEF2A transgenic adult mice showed reduced transient outward K⁺ currents, consistent with the alterations in gene expression observed in transgenic mice and partially suggesting a proximal mechanism underlying MEF2-dependent cardiomyopathy.

Received for publication, September 16, 2005 , and in revised form, January 27, 2006.

^* This work was supported in part by the National Institutes of Health (to J. D. M.). 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 Tables 1–4.

¹ Supported by Predoctoral Fellowship 0215048B from the American Heart Association, Ohio Valley Affiliate Branch.

² Supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada, the Training Program in Cardiovascular Research: Molecules to Humans, Heart Failure to Prevention (TACTICS)-Canadian Institutes of Health Research Program at the University of Toronto, and the Faculty of Medicine at the University of Toronto.

³ Supported by a research grant from the Canadian Institutes of Health and a career investigatorship from the Heart and Stroke Foundation of Ontario.

⁴ Established Investigator of the American Heart Association. To whom correspondence should be addressed: Div. of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229. Fax: 513-636-5958; E-mail: jeff.molkentin{at}cchmc.org.

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