title: Agonists at PPAR-gamma suppress angiotensin II-induced production of plasminogen activator inhibitor-1 and extracellular matrix in rat cardiac fibroblasts.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor (PPAR)-gamma ligands have been shown to inhibit cardiac fibrosis. However, the underlying mechanisms are poorly understood. We investigated the regulation by PPAR-gamma ligands of angiotensin (Ang) II-induced plasminogen activator inhibitor (PAI)-1, extracellular matrix (ECM) production and cell growth in cardiac fibroblasts.
  
  
  METHODS
  The effects of PPAR-gamma ligands on Ang II-induced PAI-1, ECM expression and cell growth were assessed in primary-cultured rat cardiac fibroblasts; cardiac PAI-1 and ECM production was examined in Ang II-infused rats.
  
  
  RESULTS
  In growth-arrested cardiac fibroblasts, PPAR-gamma ligands rosiglitazone and 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) dose-dependently attenuated Ang II-induced cell proliferation and expression of PAI-1, collagen type-I, collagen type-III and fibronectin. An accompanying increase in PPAR-gamma expression and activation was also observed. These suppressive effects were attenuated by the PPAR-gamma antagonists GW9662 and bisphenol A diglycidyl ether (BADGE). Moreover, rosiglitazone and 15d-PGJ2 inhibited in part the expression and phosphorylation of Ang II-induced transforming growth factor (TGF)-beta1, Smad2/3 and c-Jun NH(2)-terminal kinase (JNK). Ang II infusion in rats markedly increased left ventricular production of PAI-1, collagen and fibronectin, with a concurrent increase in the ratios of heart weight/body weight and left ventricle weight/body weight. Co-treatment with rosiglitazone significantly decreased these levels and upregulated PPAR-gamma expression.
  
  
  CONCLUSIONS
  Rosiglitazone and 15d-PGJ2 suppress Ang II-induced production of PAI-1 and ECM probably via interactions between PPAR-gamma and TGF-beta1/Smad2/3 and JNK signalling pathways. It is suggested that PPAR-gamma and its ligands may have potential applications in preventing cardiac fibrosis.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
authors.forename: G-H
authors.initials: GH
authors.lastname: Hao
authors.forename: X-L
authors.initials: XL
authors.lastname: Niu
authors.forename: D-F
authors.initials: DF
authors.lastname: Gao
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.forename: N-P
authors.initials: NP
authors.lastname: Wang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; D000804:Angiotensin II; D015230:Prostaglandin D2