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

Eric M. Small, Jeffrey E. Thatcher, Lillian B. Sutherland, Hideyuki Kinoshita, Robert D. Gerard, James A. Richardson, J. Michael Dimaio, Hesham Sadek, Koichiro Kuwahara, Eric N. Olson

Research output: Contribution to journalArticle

236 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)294-304
Number of pages11
JournalCirculation research
Volume107
Issue number2
DOIs
StatePublished - Jul 23 2010

Keywords

  • MRTF-A
  • collagen
  • fibrosis
  • myocardial infarction
  • myofibroblast
  • transcription

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction'. Together they form a unique fingerprint.

  • Cite this