标题：PPAR-gamma activation by rosiglitazone suppresses angiotensin II-mediated proliferation and phenotypictransition in cardiac fibroblasts via inhibition of activation of activator protein 1
作者：Hou, Xiaoyang; Zhang, Ying; Shen, Ying H.; Liu, Tongbao; Song, Shangming; Cui, Lianqun; Bu, Peili
作者机构：[Hou, Xiaoyang; Liu, Tongbao; Song, Shangming; Cui, Lianqun] Shandong Univ, Prov Hosp, Dept Cardiol, Jinan 250020, Peoples R China.; [Hou, Xiaoyang; 更多
通讯作者地址：[Bu, PL]Shandong Univ, Qilu Hosp, Chinese Minist Educ, Key Lab Cardiovasc Remodeling & Funct Res, Jinan 250012, Shandong, Peoples R China.
来源：EUROPEAN JOURNAL OF PHARMACOLOGY
关键词：Differentiation; Peroxisome proliferator-activated receptor-gamma;; Cardiac fibroblast; Cyclin D-1; Activator protein-1
摘要：Cardiac fibroblasts play an important role in myocardial remodeling by proliferating, differentiating, and secreting extracellular matrix proteins. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands haw been reported to have a number of cardioprotective properties. However, the mechanism under-lying this protective effect has not yet been elucidated. The purpose of the present study was to investigate the effect of rosiglitazone on angiotensin II-induced cardiac fibroblast proliferation and differentiation. Cardiac fibroblasts were stimulated with angiotensin II (10(-7) M) in the presence or absence of rosiglitazone (10(-5) nM). Pretreatment of cardiac fibroblasts with rosiglitazone significantly inhibited angiotensin II-induced cardiac fibroblast proliferation and profibrotic phenotypes differentiation and, thus, reduced the overall production of collagen components. PPAR-gamma antagonist GW9662 significantly inhibited these effects of rosiglitazone, suggesting that these effects of rosiglitazone were PPAR-gamma-dependent. To investigate the mechanisms involved, we found that PPAR-gamma activation by rosiglitazone inhibited the formation of c-fos/c-jun heterodimers and expression of activator protein 1 induced by ANG II and thus inhibited transcription of the downstream genes involved in CFs proliferation and differentiation. Our data suggests PPAR-gamma activation could have an anti-fibrotic effect through limiting cardiac fibroblast proliferation and differentiation, which are the critical steps in the pathogenesis of cardiac fibrosis. (C) 2013 Elsevier B.V. All rights reserved.