Agonists at PPAR-γ suppress angiotensin II-induced production of plasminogen activator inhibitor-1 and extracellular matrix in rat cardiac fibroblasts

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.