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The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice
Yuri Kim, … , Rhonda Bassel-Duby, Eric N. Olson
Yuri Kim, … , Rhonda Bassel-Duby, Eric N. Olson
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):124-132. https://doi.org/10.1172/JCI33255.
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Research Article Cardiology Article has an altmetric score of 9

The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice

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Abstract

The adult heart responds to excessive neurohumoral signaling and workload by a pathological growth response characterized by hypertrophy of cardiomyocytes and activation of a fetal program of cardiac gene expression. These responses culminate in diminished pump function, ventricular dilatation, wall thinning, and fibrosis, and can result in sudden death. Myocyte enhancer factor–2 (MEF2) transcription factors serve as targets of the signaling pathways that drive pathological cardiac remodeling, but the requirement for MEF2 factors in the progression of heart disease in vivo has not been determined. MEF2A and MEF2D are the primary MEF2 factors expressed in the adult heart. To specifically determine the role of MEF2D in pathological cardiac remodeling, we generated mice with a conditional MEF2D allele. MEF2D-null mice were viable, but were resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and β-chronic adrenergic stimulation. Furthermore, we show in a transgenic mouse model that forced overexpression of MEF2D was sufficient to drive the fetal gene program and pathological remodeling of the heart. These results reveal a unique and important function for MEF2D in stress-dependent cardiac growth and reprogramming of gene expression in the adult heart.

Authors

Yuri Kim, Dillon Phan, Eva van Rooij, Da-Zhi Wang, John McAnally, Xiaoxia Qi, James A. Richardson, Joseph A. Hill, Rhonda Bassel-Duby, Eric N. Olson

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Figure 2

Blunted hypertrophy of Mef2d mutant mice following TAC.

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Blunted hypertrophy of Mef2d mutant mice following TAC.
               
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(A) HW/TL ratios (±SEM) of WT and Mef2d mutant mice were determined 21 days after TAC. (B) Hearts from WT and Mef2d mutant mice subjected to either a sham operation or pressure overload (TAC) are shown at the top. Histological sections stained with Masson’s trichrome are shown on the bottom. Masson’s trichrome staining of WT and Mef2d mutant hearts indicates lack of fibrosis in Mef2d–/– hearts in response to pressure overload by TAC. Scale bars: 1 mm (middle panel); 40 μm (bottom panel). (C) Mean cross-sectional area of cardiomyocytes (±SEM) in WT and Mef2d mutant mice was measured 21 days after TAC. (D) Using morphometric analysis of picrosirius red stained heart sections, the amount of myocardial fibrosis was assessed. Fibrosis was apparent in the hearts of WT mice following TAC. In contrast, virtually no fibrosis was detected in the hearts of Mef2d mutant mice. Values indicate fold changes of fibrosis in each group compared with a group of sham-operated WT mice (±SEM).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 5 patents
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