title: Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling.
abstract: BACKGROUND
  Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-beta/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses.
  
  
  RESULTS
  We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3-/- mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-beta-mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-beta responses.
  
  
  CONCLUSIONS
  Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.
authors.affiliation: Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Bujak
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ren
authors.forename: Hyuk Jung
authors.initials: HJ
authors.lastname: Kweon
authors.forename: Marcin
authors.initials: M
authors.lastname: Dobaczewski
authors.forename: Anilkumar
authors.initials: A
authors.lastname: Reddy
authors.forename: George
authors.initials: G
authors.lastname: Taffet
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D003971:Diastole / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015425:Myocardial Reperfusion; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism*; D015996:Survival Rate; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D018925:Chemokines; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D003094:Collagen; D020781:Matrix Metalloproteinase 1