title: Early and delayed tranilast treatment reduces pathological fibrosis following myocardial infarction.
abstract: BACKGROUND
  Tranilast has been shown to inhibit TGFβ1-related fibrosis and organ failure in various disease models. We sought to examine the effects of tranilast on left ventricular (LV) remodelling post-MI.
  
  
  METHODS
  Following coronary artery ligation, Sprague Dawley rats were randomised to receive tranilast (300mg/kg/d, p.o.) or vehicle control over one of two treatment periods: (1) from 24h until seven days post-MI, (2) from seven days to 28 days post-MI. Cardiac tissue was harvested for molecular, immunohistochemical and cell culture analyses.
  
  
  RESULTS
  Tranilast treatment of MI rats from 24h until seven days post-MI reduced myocardial collagen content, α1 (I) procollagen, TGFβ1 and CTGF mRNA transcripts, monocyte/macrophage infiltration and exacerbated infarct expansion compared with vehicle-treatment. Delaying the commencement of tranilast treatment to seven days post-MI attenuated myocardial fibrosis, gene expression of α1(I) procollagen, α1(III) procollagen, fibronectin, TGFβ1 and CTGF mRNA transcripts, and monocyte/macrophage infiltration at 28d compared to vehicle-treatment, without detriment to infarct healing. Extended post-MI also preserved LV infarct size. In cultures of rat cardiac fibroblasts, tranilast attenuated TGFβ1-stimulated fibrogenesis.
  
  
  CONCLUSIONS
  Tranilast inhibits myocardial TGFβ1 expression, fibrosis in rat post-MI and collagen production in cardiac fibroblasts. While tranilast intervention from 24h post-MI exacerbated infarct expansion, delaying the commencement of treatment to seven days post-MI impeded LV remodelling.
authors.affiliation: Department of Epidemiology & Preventive Medicine, Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: See
authors.affiliation: Department of Epidemiology & Preventive Medicine, Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Victoria 3004, Australia. Electronic address: masataka.watanabe@monash.edu.
authors.forename: Masataka
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Epidemiology & Preventive Medicine, Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Kompa
authors.affiliation: Department of Epidemiology & Preventive Medicine, Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Bing H
authors.initials: BH
authors.lastname: Wang
authors.affiliation: Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Boyle
authors.affiliation: Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.affiliation: Department of Epidemiology & Preventive Medicine, Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis / Q000096:biosynthesis; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000235:genetics; D003331:Coronary Vessels; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects*; D008026:Ligation; D008264:Macrophages; D008297:Male; D009000:Monocytes; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000737:chemistry / Q000473:pathology*; D009929:Organ Size; D010766:Phosphorylation; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects*; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C526316:CCN2 protein, rat; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D012333:RNA, Messenger; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D062367:ortho-Aminobenzoates; D055513:Connective Tissue Growth Factor; D003094:Collagen; C012293:tranilast