TY - JOUR
T1 - Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction
AU - Small, Eric M.
AU - Thatcher, Jeffrey E.
AU - Sutherland, Lillian B.
AU - Kinoshita, Hideyuki
AU - Gerard, Robert D.
AU - Richardson, James A.
AU - Dimaio, J. Michael
AU - Sadek, Hesham
AU - Kuwahara, Koichiro
AU - Olson, Eric N.
PY - 2010/7/23
Y1 - 2010/7/23
N2 - 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.
AB - 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.
KW - MRTF-A
KW - collagen
KW - fibrosis
KW - myocardial infarction
KW - myofibroblast
KW - transcription
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U2 - 10.1161/CIRCRESAHA.110.223172
DO - 10.1161/CIRCRESAHA.110.223172
M3 - Article
C2 - 20558820
AN - SCOPUS:77955173404
SN - 0009-7330
VL - 107
SP - 294
EP - 304
JO - Circulation research
JF - Circulation research
IS - 2
ER -