Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor-β1 in cultured cardiac fibroblasts

被引：39
作者：
Shyu, Kou-Gi [2 ,3 ]
Wang, Bao-Wei [2 ,4 ]
Chen, Wei-Jan [5 ]
Kuan, Peiliang [2 ]
Hung, Chi-Ren [1 ]
机构：
[1] Shin Kong Wu Ho Su Mem Hosp, Div Cardiovasc Surg, Taipei, Taiwan
[2] Shin Kong Wu Ho Su Mem Hosp, Div Cardiol, Taipei, Taiwan
[3] Taipei Med Univ, Grad Inst Clin Med, Coll Med, Taipei, Taiwan
[4] Fu Jen Catholic Univ, Sch Med, Taipei, Taiwan
[5] Chang Gung Mem Hosp, Cardiovasc Div 1, Linkou, Taipei County, Taiwan
来源：
EUROPEAN JOURNAL OF HEART FAILURE | 2010年 / 12卷 / 03期
关键词：
Fibroblast; Endoglin; Fibrosis; Statin; Transforming growth factor-beta 1; GROWTH-FACTOR-BETA; NITRIC-OXIDE SYNTHASE; REDUCTASE INHIBITOR; COLLAGEN-SYNTHESIS; UP-REGULATION; FIBROSIS; HYPERTROPHY; PITAVASTATIN; FLUVASTATIN; INDUCTION;
D O I：
10.1093/eurjhf/hfq011
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
Transforming growth factor-beta 1 (TGF-beta 1) and endoglin play a causal role in promoting cardiac fibrosis. Atorvastatin has been shown to have an inhibitory effect on cardiac fibroblasts in vitro. However, the effects of statins on TGF-beta 1 and endoglin are poorly understood. We therefore sought to investigate the molecular mechanisms of atorvastatin on endoglin expression after TGF-beta 1 stimulation in cardiac fibroblasts. Cultured cardiac fibroblasts were obtained from adult male Sprague-Dawley rat hearts. TGF-beta 1 stimulation increased endoglin and collagen I expression and atorvastatin inhibited the induction of endoglin and collagen I by TGF-beta 1. Phosphatidylinositol-3 kinase (PI-3) and Akt inhibitors (wortmannin and Akt inhibitor X) completely attenuated the endoglin protein expression induced by TGF-beta 1. TGF-beta 1 induced phosphorylation of PI-3 kinase and Akt, while atorvastatin and wortmannin and Akt inhibitor X inhibited the phosphorylation of PI-3 kinase and Akt induced by TGF-beta 1. The gel shift and promoter activity assay showed that TGF-beta 1 increased Smad3/4-binding activity and endoglin promoter activity, while wortmannin and atorvastatin inhibited the Smad3/4-binding activity and endoglin promoter activity induced by TGF-beta 1. TGF-beta 1 increased collagen I protein expression, while endoglin siRNA attenuated collagen I protein expression induced by TGF-beta 1. Atorvastatin decreased left ventricular TGF-beta 1, endoglin, and collagen I protein expression and fibrotic area in a rat model of volume overload heart failure. Atorvastatin inhibits endoglin expression through the inhibition of PI-3 kinase, Akt, and Smad3 phosphorylation, and reduced Smad3/4 binding activity and endoglin promoter activity in cardiac fibroblasts.
引用
收藏
页码：219 / 226
页数：8
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