非诺贝特抑制血管紧张素Ⅱ所诱导的心脏成纤维细胞骨桥蛋白表达升高

中国临床药理学与治疗学 ›› 2010, Vol. 15 ›› Issue (11): 1211-1215.

非诺贝特抑制血管紧张素Ⅱ所诱导的心脏成纤维细胞骨桥蛋白表达升高

李文举, 石苗茜, 欧东波, 丁璐, 牛晓琳, 刘雄涛, 郑强荪

第四军医大学唐都医院心内科,西安 710038,陕西

收稿日期:2010-08-16 修回日期:2010-10-12 出版日期:2010-11-26 发布日期:2020-09-16
通讯作者: 郑强荪,男,教授,主任医师,博士研究生导师,研究方向:心衰的机制与临床研究。Tel: 029-84777422 E-mail: qiangsunzheng@gmail.com
作者简介:李文举,男,硕士研究生,研究方向:心衰的机制与临床研究。Tel: 15829739527 E-mail: adrianli@foxmail.com

Inhibition of fenofibrate on angiotensinⅡ-induced high expression of osteopontin in cardiac fibroblasts

LI Wen-ju, SHI Miao-qian, OU Dong-bo, DING Lu, LIU Xiao-lin, NIU Xiong-tao, ZHENG Qiang-sun

Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, Shaanxi, China

Received:2010-08-16 Revised:2010-10-12 Online:2010-11-26 Published:2020-09-16

摘要/Abstract

摘要： 目的: 探讨过氧化物酶体增殖物激活受体α(PPARα)激动剂非诺贝特对血管紧张素Ⅱ(AngII)诱导的心脏成纤维细胞骨桥蛋白表达升高的影响。方法: 分离并传代培养SD大鼠乳鼠心脏成纤维细胞,使用不同浓度(0、25、50、100 μmol/L)的非诺贝特预处理 1 h 后,加入AngII作用 24 h。分别采用实时定量PCR法和Western blotting技术检测骨桥蛋白mRNA和蛋白表达情况。结果: 非诺贝特显著抑制AngII诱导的心脏成纤维细胞骨桥蛋白mRNA及蛋白的表达,并且呈剂量依赖性。结论: 非诺贝特对心脏成纤维细胞中骨桥蛋白的表达具有明显的抑制作用,这可能是其在心血管系统发挥抗纤维化和抗炎作用的部分机制。

关键词: 心肌纤维化, 心脏成纤维细胞, 非诺贝特, 骨桥蛋白

Abstract: AIM: To investigate the effects of fenofibrate, peroxisome proliferator-activated receptor α (PPARα) agonist, on the up-regulation of angiotensin II (Ang II)-induced osteopontin in rat cardiac fibroblasts. METHODS: Isolated cardiac fibroblasts of neonatal Sprague-Dawley rat were pretreated with various concentrations of fenofibrate (0, 25, 50 and 100 μmmol/L) for 1 hour. Then Ang II were added into cells for 24 hours. The expression of osteopontin was measured by real-time quantitative RT-PCR and Western blotting, separately. RESULTS: Significant inhibitory effects of fenofibrate on Ang II-induced high expression of osteopontin were observed in cardiac fibroblasts and the effect was dose dependent (P<0.05). CONCLUSION: The present data suggests that fenofibrate can down-regulate the level of osteopontin in rat cardiac fibroblasts, which may explain the anti-inflammatory and anti-fibrosis effects of fenofibrate in the cardiovascular system.

Key words: Myocardial fibrosis, Cardiac fibroblast, Fenofibrate, Osteopontin

中图分类号:

R965.2

李文举, 石苗茜, 欧东波, 丁璐, 牛晓琳, 刘雄涛, 郑强荪. 非诺贝特抑制血管紧张素Ⅱ所诱导的心脏成纤维细胞骨桥蛋白表达升高[J]. 中国临床药理学与治疗学, 2010, 15(11): 1211-1215.

LI Wen-ju, SHI Miao-qian, OU Dong-bo, DING Lu, LIU Xiao-lin, NIU Xiong-tao, ZHENG Qiang-sun. Inhibition of fenofibrate on angiotensinⅡ-induced high expression of osteopontin in cardiac fibroblasts[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(11): 1211-1215.

参考文献

[1] 曾爱辉,谭茗月. 骨桥蛋白与慢性心力衰竭的关系研究进展[J]. 中国现代药物应用,2009,3(18): 183-185.
[2] 李传保,卜培莉. 非诺贝特与高血压心肌重构[J]. 中国老年学杂志,2008,28(1): 100-102.
[3] Schneider S, Yochim J, Brabender J, et al. Osteopontin but not osteonectin messenger RNA expression is a prognostic marker in curatively resected non-small cell lung cancer [J]. Clin Cancer Res, 2004, 10(5): 1588-1596.
[4] Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method [J]. Methods, 2001, 25(4):402-408.
[5] Vera T, Taylor M, Bohman Q, et al. Fenofibrate prevents the development of angiotensin II-dependent hypertension in mice [J]. Hypertension, 2005, 45(4): 730-735.
[6] Wang Y, Wang Y, Yang Q, et al. Effects of bezafibrate on the expression of endothelial nitric oxide synthase gene and its mechanisms in cultured bovine endothelial cells [J]. Atherosclerosis, 2006, 187(2): 265-273.
[7] Ichihara S, Obata K, Yamada Y, et al. Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors [J]. Mol Cell Cardiol, 2006, 41(2): 318-329.
[8] Brigadeau F, Gele P, Wibaux M, et al. The PPARalpha activator fenofibrate slows down the progression of the left ventricular dysfunction in porcine tachycardia-induced cardiomyopathy [J]. J Cardiovasc Pharmacol, 2007, 49(6): 408-415.
[9] Lebrasseur NK, Duhaney TA, De Silva DS, et al. Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension [J]. Hypertension, 2007, 50(3): 489-496.
[10] Ogata T, Miyauchi T, Irukayama-Tomobe Y, et al. The peroxisome proliferator-activated receptor alpha activator fenofibrate inhibits endothelin-1-induced cardiac fibroblast proliferation[J]. J Cardiovasc Pharmacol, 2004, 44 Suppl 1: S279-282.
[11] 孙国举,谢秀梅,邢莹,等. 非诺贝特对溶血卵磷脂诱导的血管内皮细胞增生及凋亡的影响[J]. 中国临床药理学与治疗学,2006,11(5): 535-539.
[12] 罗志建,湛晓勤. 骨桥蛋白与感染性疾病[J].国际呼吸杂志,2009,29(10): 616-620.
[13] Singh M, Foster CR, Dalal S, et al. Osteopontin: role in extracellular matrix deposition and myocardial remodeling post-MI [J]. J Mol Cell Cardiol, 2010, 48(3): 538-543.
[14] Xie Z, Singh M, Singh K. ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiacfibroblasts [J]. J Cell Physiol, 2004, 198(3):399-407.
[15] Lenga Y, Koh A,Perera AS, et al. Osteopontin expression is required for myofibroblast differentiation [J]. Circ Res, 2008, 102(3): 319-327.
[16] Collins AR, Schnee J, Wang W, et al. Osteopontin modulates angiotensin II-induced fibrosis in the intact murine heart [J]. J Am Coll Cardiol, 2004, 43(9): 1698-1705.
[17] Trueblood NA, Xie Z, Communal C, et al. Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin [J]. Circ Res, 2001, 88(10): 1080-1087.
[18] Xie Z, Singh M, Siwik DA, et al. Osteopontin inhibits interleukin-1beta-stimulated increases in matrix metalloproteinase activity in adult rat cardiac fibroblasts: role of protein kinase C-zeta [J]. J Biol Chem, 2003, 278(49): 48546-48552.
[19] Nakamachi T, Nomiyama T, Gizard F, et al. PPARalpha agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes [J]. Diabetes, 2007, 56(6): 1662-1670.