Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction.

Abstract:

RATIONALE:Myocardial infarction (MI) results in loss of cardiac myocytes in the ischemic zone of the heart, followed by fibrosis and scar formation, which diminish cardiac contractility and impede angiogenesis and repair. Myofibroblasts, a specialized cell type that switches from a fibroblast-like state to a contractile, smooth muscle-like state, are believed to be primarily responsible for fibrosis of the injured heart and other tissues, although the transcriptional mediators of fibrosis and myofibroblast activation remain poorly defined. Myocardin-related transcription factors (MRTFs) are serum response factor (SRF) cofactors that promote a smooth muscle phenotype and are emerging as components of stress-responsive signaling. OBJECTIVE:We aimed to examine the effect of MRTF-A on cardiac remodeling and fibrosis. METHODS AND RESULTS:Here, we show that MRTF-A controls the expression of a fibrotic gene program that includes genes involved in extracellular matrix production and smooth muscle cell differentiation in the heart. In MRTF-A-null mice, fibrosis and scar formation following MI or angiotensin II treatment are dramatically diminished compared with wild-type littermates. This protective effect of MRTF-A deletion is associated with a reduction in expression of fibrosis-associated genes, including collagen 1a2, a direct transcriptional target of SRF/MRTF-A. CONCLUSIONS:We conclude that MRTF-A regulates myofibroblast activation and fibrosis in response to the renin-angiotensin system and post-MI remodeling.

journal_name

Circ Res

journal_title

Circulation research

authors

Small EM,Thatcher JE,Sutherland LB,Kinoshita H,Gerard RD,Richardson JA,Dimaio JM,Sadek H,Kuwahara K,Olson EN

doi

10.1161/CIRCRESAHA.110.223172

subject

Has Abstract

pub_date

2010-07-23 00:00:00

pages

294-304

issue

2

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.110.223172

journal_volume

107

pub_type

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