【摘要】 目的研究过氧化物酶体增殖物激活受体-γ(PPAR-γ)激活对心肌纤维化的影响是否与血管紧张素Ⅱ(AngⅡ)-Ets-1通路有关。方法体外培养大鼠心脏成纤维细胞(CFs),分为对照组、AngⅡ组、AngⅡ+不同浓度rosiglitazone处理组、AngⅡ+不同PPAR-γ激动剂组、AngⅡ+不同PPAR-γ拮抗剂组,采用实时定量RT-q PCR、Western blot等检测Ets-1、CTGF mRNA及蛋白表达,并测定TGF-β1和Smad2/3的表达及磷酸化水平。结果在CFs中,AngⅡ诱导Ets-1 mRNA及蛋白表达(P<0.05),上调Ets-1下游靶基因CTGF的蛋白的表达(P<0.05),增加TGF-β1和Smad2/3的表达及磷酸化(P<0.05)。PPAR-γ激动剂rosiglitazone,15d-PGJ2抑制AngⅡ诱导的Ets-1 mRNA及蛋白的表达(P<0.05),下调AngⅡ诱导的CTGF蛋白表达(P<0.05),部分阻断AngⅡ诱导的TGF-β1的表达、Smad2/3的表达及磷酸化(P<0.05)。PPAR-γ拮抗剂GW9662及BADGE均可阻断rosiglitazone对Ets-1及CTGF表达的抑制作用(P<0.05)。结论 PPAR-γ激活主要通过TGF-β1/Smad2/3通路介导抑制AngⅡ诱导的大鼠CFs转录因子Ets-1的过表达。更多还原

【Abstract】 Objective To investigate whether peroxisome proliferator-activated receptor-γ( PPAR-γ) activation inhibits cardiac fibrosis through the angiotensin Ⅱ( AngⅡ)-Ets-1 pathway. Methods Primary cultured cardiac fibroblasts( CFs) of rats were divided into these groups: control,AngⅡ,Ang Ⅱ + rosiglitazone,Ang Ⅱ + other PPAR-γ ligands,AngⅡ + PPAR-γ antagonists. The change in expression of Ets-1,connective tissue growth factor( CTGF),transforming growth factor( TGF)-β1 and Smad2 /3 was assessed by using real-time RT-PCR and western blot. Results In growth-arrested CFs,AngⅡ induced the expression of Ets-1 mRNA and protein( P < 0. 05),up-regulated expression of Ets-1 down stream target CTGF( P < 0. 05),enhanced the expression of TGF-β1and the expression and phosphorylation of Smad2 /3( P < 0. 05). PPAR-γ ligands rosiglitazone and 15d-PGJ2 attenuated the expression of Ang Ⅱ-induced Ets-1 mRNA and protein( P < 0. 05),decreased the induction of CTGFby AngⅡ( P < 0. 05),inhibited expression of TGF-β1 and the expression and phosphorylation of Smad2 /3 induced by AngⅡ( P < 0. 05). These suppressive effects on Ets-1 and CTGF were attenuated by PPAR-γ antagonists GW9662 and BADGE( P < 0. 05). Conclusions Activation of PPAR-γ inhibits AngⅡ-induced Ets-1 expression via the TGF-β1 / Smad2 /3 signaling pathway.更多还原