title: Simvastatin inhibits homocysteine-induced CRP generation via interfering with the ROS-p38/ERK1/2 signal pathway in rat vascular smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy, Zibo Central Hospital, Zibo, China; Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Pang
authors.affiliation: Department of Clinical Pharmacy, Zibo Central Hospital, Zibo, China.
authors.forename: Jigang
authors.initials: J
authors.lastname: Si
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, China.
authors.forename: Shouzhu
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Clinical Pharmacy, Zibo Central Hospital, Zibo, China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, China. Electronic address: ljt@mail.xjtu.edu.cn.
authors.forename: Juntian
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D002097:C-Reactive Protein / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D017382:Reactive Oxygen Species; D006710:Homocysteine; D002097:C-Reactive Protein; D019821:Simvastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Atherosclerosis; C-reactive protein; Homocysteine; Inflammation; Simvastatin