Cer—SPK—S1P通路在动脉粥样硬化中的作用及田黄片的干预研究

Atherosclerosis (AS) is a common disease with high morbidity and mortality. The current clinical first-line drug for AS is statins, which can reduce only about 30% of acute coronary events by inhabiting LDL cholesterol synthesis. Therefore more effective drugs and targets are necessarily to be developed. Preliminary studies showed that THP, a proved recipe of Chinese Medicine, had the comprehensive effects of anti-atherosclerosis, improving lipid profile, inhibiting macrophage foaming and antioxidant. Subsequently THP got the patent protection, and had good prospects. The latest metabolomics study investigated that THP could decrease blood sphingomyelin (SM) and increase 1- sphingosine phosphate (S1P). Then whether regulation of SM and S1P is an alternative pathway of anti-atherosclerosis? What about the role of the key enzyme of sphingosine kinase (SPK) which regulating the metabolism of SM and S1P in the AS pathophysiology? This study intends to reveals key role of SPK in AS developing, clarify anti-atherosclerotic mechanism of THP , both in vivo and in vitro,to threw lights in the development of high quality candidate drug and potential biological targets.

动脉粥样硬化（AS）发病率高、危害大，目前临床一线治疗药物为针对低密度胆固醇合成的他汀类药物，仅能降低急性冠脉事件30%左右，急需寻找更有效的防治药物和作用靶点。田黄片（THP）为临床验方制剂，前期研究显示其具有改善血脂谱、防治脂肪肝、抑制动脉粥样硬化形成及抗氧化等综合作用，获得了专利保护，具良好应用前景。新近代谢组学研究又发现其还具有降低血鞘磷脂（SM），升高1-磷酸鞘氨醇（S1P）作用。那么，在其抑制巨噬细胞泡沫化，调节血脂代谢、抗氧化能力等机制外，调节SM、S1P是否是其抗AS又一新机制？鞘氨醇激酶（SPK）作为调控 SM与 S1P 代谢平衡的关键酶，在动脉粥样硬化中扮演什么角色？本课题拟将细胞实验与动物实验相结合，揭示SPK在AS中的关键作用，阐明THP抗AS作用新机制，为临床有效干预AS提供优质候选药物和潜在生物靶标，拓展AS防治思路和视野。

动脉粥样硬化（AS）发病率高、危害大，目前临床一线治疗药物为针对低密度胆固醇合成的他汀类药物，仅能降低急性冠脉事件30%左右，急需寻找更有效的防治药物和作用靶点。田黄片（THP）为临床验方制剂，前期研究显示其具有改善血脂谱、防治脂肪肝、抑制动脉粥样硬化形成及抗氧化等综合作用，获得了专利保护，具良好应用前景。本项目在此基础上，进一步开展田黄片药效学及基于S1P—S1PR1通路，探究其抗动脉粥样硬化新机制，初步阐明S1P—S1PR1通路在抗AS中的角色，为筛选抗AS的药物新靶点提供新思路。. 研究结果表明，田黄片能显著改善ApoE-/-小鼠血脂水平，降低ApoE-/-小鼠主动脉和主动脉瓣部斑块面积，抑制AS发展，其作用机制可能为：降低泡沫细胞胆固醇摄入受体CD36表达，升高胆固醇逆转运受体ABCG1、ABCA1、SR-BI表达；田黄片还能显著升高S1P含量和促进S1PR1、LXRa表达，可能是其抗AS的又一新途径。. 本项目从整体动物——动脉粥样硬化公认模型ApoE基因敲除小鼠和细胞水平，从AS形成的关键环节——巨噬细胞胆固醇流出，选择检测金指标——主动脉斑块面积，考察S1P可能介导HDL逆胆固醇转运而抗AS作用关键靶点——ABCA 1、SR-BI，阐明田黄片抗AS作用及其作用新机制。既能为防治动脉粥样硬化提供潜在药物，又能为筛选抗动脉粥样药物提供可能新靶点，具有重要的理论价值和临床应用前景。