Pang Xiaoming, Si Jigang, Xu Shouzhu, Li Yuxia, Liu Juntian
Department of Clinical Pharmacy, Zibo Central Hospital, Zibo, China; Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, China.
Department of Clinical Pharmacy, Zibo Central Hospital, Zibo, China.
Vascul Pharmacol. 2017 Jan;88:42-47. doi: 10.1016/j.vph.2016.12.001. Epub 2016 Dec 16.
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.
炎症在动脉粥样硬化的形成和发展过程中起着关键作用。作为最具代表性的炎症标志物，C反应蛋白（CRP）直接参与动脉粥样硬化的起始和发展。血浆中同型半胱氨酸（Hcy）水平升高是动脉粥样硬化的一个独立危险因素。我们之前报道过，Hcy通过刺激血管平滑肌细胞（VSMCs）中CRP的表达产生促炎作用。本研究观察了辛伐他汀对VSMCs中Hcy诱导的CRP表达的影响及其分子机制。体外实验表明，用辛伐他汀预处理VSMCs可呈浓度依赖性地降低Hcy诱导的CRP的mRNA和蛋白表达。体内结果显示，辛伐他汀不仅在mRNA和蛋白水平上抑制血管壁中CRP的表达，还降低了高同型半胱氨酸血症大鼠的循环CRP水平。进一步的实验表明，辛伐他汀减少了Hcy诱导的活性氧（ROS）生成，改善了Hcy激活的ERK1/2和p38的磷酸化，并拮抗了Hcy下调的VSMCs中过氧化物酶体增殖物激活受体γ的表达。这些数据表明，辛伐他汀能够抑制VSMCs中Hcy诱导的CRP生成，从而通过干扰ROS-MAPK信号通路减轻血管炎症反应。本研究结果为理解辛伐他汀潜在的抗炎和抗动脉粥样硬化作用提供了新的证据。由于血浆中高水平的Hcy与动脉粥样硬化形成相关并介导心血管风险，我们的研究结果强调了他汀类药物治疗动脉粥样硬化中高同型半胱氨酸血症的重要性和必要性。
