他汀类药物通过调脂、抗动脉粥样硬化、血管内皮保护等多种机制发挥心脑血管保护作用，其效应受遗传因素影响。内源性NO合酶抑制物非对称二甲基精氨酸（ADMA）通过抑制NO生成，参与心血管疾病发病机制，影响药物反应性，并受他汀类药物调节。本项目在前期研究发现ADMA关键代谢酶DDAH1和AGXT2编码基因的功能性遗传多态影响心脑血管疾病易感性或预后的基础上，提出DDAH1和AGXT2基因多态性可能影响辛伐他汀的心脑血管保护效应。项目拟通过严格设计的临床试验和前瞻性流行病学调查，查明DDAH1和AGXT2功能性遗传变异对辛伐他汀心脑血管保护作用及其改善动脉粥样硬化性脑梗死预后的影响基础上，应用原代培养的人脐静脉内皮细胞（HUVEC）和内皮细胞株，研究两个基因的遗传变异影响辛伐他汀心脑血管保护作用的分子机制；旨在发现影响辛伐他汀心血管保护效应新的遗传标记，为个体化应用辛伐他汀、提高其临床疗效奠定基础。

Statins show cardiovascular and cerebrovascular protective effects through mechanisms including lipid-lowering, anti-atherosclerosis, and vascular endothelial protection. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in the pathophysiology of cardiovascular diseases through inhibiting NO production. Plasma ADMA level can affect statins responses and is also regulated by statins. Based on our previous findings that functional polymorphisms genes coding DDAH1 and AGXT2, two genes coding enzymes play critical role in ADMA metabolism, are associated with risks for and prognosis of cardiovascualr and cerebrovascular diseases, we assumed that the polymorphisms in these genes may affect the cardiovascular protective effects of simvastatin. By strictly designed clinical trial and prospective epidemiological study, we would firstly make clear whether functional polymorphisms in DDAH1 and AGXT2 affect the cardiovascular and cerebrovascular protectve effects of simvastatin as well as its effects in improving the prognosis of ischemic stroke due to atherosclerosis. And then,the mechanisms by which polymorphisms in the two genes affecting the cardiovascular protective effective of simvastatin would be investigated in primarily cultured HUVEC or HUVECs cell line. The study aims to identify new genetic markers that can be used to predict simvastatin response, and provide basis for personalized therapy for simvastatin in clinic.