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

作者：G‐H Hao, X‐L Niu, D‐F Gao, Jin Wei, N‐P Wang · 发表于：British Journal of Pharmacology · 年份：2008 · DOI：10.1038/bjp.2008.21 · 被引用次数：59 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors、Peroxisome Proliferator-Activated Receptors

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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...