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Agonists at PPAR‐γ suppress angiotensin II‐induced production of plasminogen activator inhibitor‐1 and extracellular matrix in rat cardiac fibroblasts
Author(s) -
Hao GH,
Niu XL,
Gao DF,
Wei J,
Wang NP
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.21
Subject(s) - rosiglitazone , endocrinology , medicine , fibronectin , angiotensin ii , plasminogen activator inhibitor 1 , chemistry , cardiac fibrosis , extracellular matrix , peroxisome proliferator activated receptor , plasminogen activator , receptor , fibrosis , biology , biochemistry
Background and purpose: Peroxisome proliferator‐activated receptor (PPAR)‐γ ligands have been shown to inhibit cardiac fibrosis. However, the underlying mechanisms are poorly understood. We investigated the regulation by PPAR‐γ ligands of angiotensin (Ang) II‐induced plasminogen activator inhibitor (PAI)‐1, extracellular matrix (ECM) production and cell growth in cardiac fibroblasts. Experimental approach: The effects of PPAR‐γ 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. Key results: In growth‐arrested cardiac fibroblasts, PPAR‐γ ligands rosiglitazone and 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 (15d‐PGJ 2 ) 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‐γ expression and activation was also observed. These suppressive effects were attenuated by the PPAR‐γ antagonists GW9662 and bisphenol A diglycidyl ether (BADGE). Moreover, rosiglitazone and 15d‐PGJ 2 inhibited in part the expression and phosphorylation of Ang II‐induced transforming growth factor (TGF)‐β1, 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‐γ expression. Conclusions and implications: Rosiglitazone and 15d‐PGJ 2 suppress Ang II‐induced production of PAI‐1 and ECM probably via interactions between PPAR‐γ and TGF‐β1/Smad2/3 and JNK signalling pathways. It is suggested that PPAR‐γ and its ligands may have potential applications in preventing cardiac fibrosis. British Journal of Pharmacology (2008) 153 , 1409–1419; doi: 10.1038/bjp.2008.21 ; published online 18 February 2008