Hao G-H, Niu X-L, Gao D-F, Wei J, Wang N-P
Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
Br J Pharmacol. 2008 Apr;153(7):1409-19. doi: 10.1038/bjp.2008.21. Epub 2008 Feb 18.
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.
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.
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.
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.
过氧化物酶体增殖物激活受体（PPAR）-γ配体已被证明可抑制心脏纤维化。然而，其潜在机制尚不清楚。我们研究了PPAR-γ配体对血管紧张素（Ang）II诱导的心脏成纤维细胞中纤溶酶原激活物抑制剂（PAI）-1、细胞外基质（ECM）产生及细胞生长的调控作用。
在原代培养的大鼠心脏成纤维细胞中评估PPAR-γ配体对Ang II诱导的PAI-1、ECM表达及细胞生长的影响；在Ang II灌注的大鼠中检测心脏PAI-1及ECM的产生情况。
在生长停滞的心脏成纤维细胞中，PPAR-γ配体罗格列酮和15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）呈剂量依赖性地减弱Ang II诱导的细胞增殖以及PAI-1、I型胶原、III型胶原和纤连蛋白的表达。同时还观察到PPAR-γ表达及激活增加。PPAR-γ拮抗剂GW9662和双酚A二缩水甘油醚（BADGE）减弱了这些抑制作用。此外，罗格列酮和15d-PGJ2部分抑制了Ang II诱导的转化生长因子（TGF）-β1、Smad2/3和c-Jun氨基末端激酶（JNK）的表达及磷酸化。向大鼠体内灌注Ang II显著增加左心室PAI-1、胶原和纤连蛋白的产生，同时心脏重量/体重及左心室重量/体重的比值增加。与罗格列酮联合治疗显著降低了这些水平并上调了PPAR-γ表达。
罗格列酮和15d-PGJ2可能通过PPAR-γ与TGF-β1/Smad2/3及JNK信号通路之间的相互作用，抑制Ang II诱导的PAI-1和ECM产生。提示PPAR-γ及其配体在预防心脏纤维化方面可能具有潜在应用价值。
