title: The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice.
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 beta-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: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
authors: Yuri
authors: Y
authors: Kim
authors: Dillon
authors: D
authors: Phan
authors: Eva
authors: E
authors: van Rooij
authors: Da-Zhi
authors: DZ
authors: Wang
authors: John
authors: J
authors: McAnally
authors: Xiaoxia
authors: X
authors: Qi
authors: James A
authors: JA
authors: Richardson
authors: Joseph A
authors: JA
authors: Hill
authors: Rhonda
authors: R
authors: Bassel-Duby
authors: Eric N
authors: EN
authors: Olson
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004108:Dilatation, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis* / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation; D018754:Ventricular Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors