Simvastatin inhibits homocysteine-induced CRP generation via interfering with the ROS-p38/ERK1/2 signal pathway in rat vascular smooth muscle cells

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• 作者：Xiaoming Pang^a ; ^b ; Jigang Si^a ; Shouzhu Xu^b ; Yuxia Li^a ; Juntian Liu^b ; ^{ljt@mail.xjtu.edu.cn}
• 关键词：Simvastatin ; Homocysteine ; C-reactive protein ; Inflammation ; Atherosclerosis
• 刊名：Vascular Pharmacology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：88
• 期：Complete
• 页码：42-47
• 全文大小：789 K
• 卷排序：88

文摘

Inflammation plays a pivotal role throughout the formation and progression of atherosclerosis. As the most representative inflammatory marker, C-reactive protein (CRP) directly participates in the initiation and development of atherosclerosis. The elevated homocysteine (Hcy) level in plasma is an independent risk factor for atherosclerosis. We previously reported that Hcy produces a pro-inflammatory effect by stimulating CRP expression in vascular smooth muscle cells (VSMCs). The present study observed the effect of simvastatin on Hcy-induced CRP expression in VSMCs and the molecular mechanisms. The in vitro experiments revealed that pretreatment of VSMCs with simvastatin decreased Hcy-induced mRNA and protein expression of CRP in a concentration-dependent fashion. The in vivo results showed that simvastatin not only inhibited CRP expression in the vessel walls in mRNA and protein levels, but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further experiments displayed that simvastatin reduced Hcy-induced reactive oxygen species (ROS) generation, ameliorated Hcy-activated phosphorylations of ERK1/2 and p38, and antagonized Hcy-downregulated peroxisome proliferator-activated receptor gamma expression in VSMCs. These data demonstrate that simvastatin is able to inhibit Hcy-induced CRP generation in VSMCs so to relieve the vascular inflammatory response via interfering with the ROS-MAPK signal pathway. The present results provide new evidence for understanding of the potential anti-inflammatory and anti-atherosclerotic effects of simvastatin. As the high level of Hcy in plasma is related to atherosclerosis formation and mediates cardiovascular risk, our findings emphasize the importance and necessity of therapy with statins for hyperhomocysteinemia in atherosclerosis.