title: Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Small
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Thatcher
authors.forename: Lillian B
authors.initials: LB
authors.lastname: Sutherland
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dimaio
authors.forename: Hesham
authors.initials: H
authors.lastname: Sadek
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000235:genetics; D002522:Chlorocebus aethiops; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; C511173:Mrtfa protein, mouse; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; C108830:Y 27632; D003094:Collagen; D054460:rho-Associated Kinases