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

Nanling L. Gong,Jian Xu,Bruce J. Aronow,Peter H. Backx,Ilona Bodi,Jeffery D. Molkentin

doi:10.1074/jbc.m510217200

Abstract

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.

Highlights

To directly investigate the ability of myocyte enhancer factor 2 (MEF2) to induce the cardiac hypertrophic response, we generated a series of cardiac-specific transgenic mice using the ␣-myosin heavy chain promoter. cDNAs encoding MEF2A and MEF2C were selected for overexpression because they have been proposed to be the predominant MEF2 isoforms expressed in the postnatal mouse
Evidence for MEF2 as a Hypertrophic Mediator—Here we presented the first experimental evidence that MEF2 transcription factors are capable of inducing cardiomyopathy in vivo
An inference to MEF2 as a hypertrophic mediator can be made based on known similarities between serum response factor (SRF) and MEF2, both of which are MADS box-containing DNA-binding factors that respond to stress, developmental, and mitogen stimulation

Summary

Introduction

Myocytes undergo developmental and pathophysiological hypertrophy in response to neuroendocrine, mitogen, and stress stimulation Such stimuli activate intracellular signal transduction cascades, resulting in the modification of transcription factor activity and the reprogramming of cardiac gene expression. A number of lines of evidence suggest that MEF2 factors might regulate inducible gene expression in response to stimuli that underlie the cardiac hypertrophic response. Hypertrophic stimulation of the adult heart is associated with activation of a number of intracellular signaling pathways, including mitogen-activated protein kinase (MAPK), calcineurin, protein kinase C, calmodulin-dependent protein kinase, insulin-like growth factor 1 pathway constituents, and altered intracellular Ca2ϩ handling [12, 13]. In-depth assessment of altered gene expression in the hearts of both MEF2A and MEF2C transgenic mice using AffymetrixTM arrays suggested a number of mechanistic associations with the cardiomyopathic disease response mediated through MEF2

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Results

Conclusion