SirT1介导硫化氢对自发性高血压大鼠血管平滑肌细胞增殖的抑制效应

项目名称： SirT1介导硫化氢对自发性高血压大鼠血管平滑肌细胞增殖的抑制效应

项目编号： No.81500325

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 孙燕

作者单位： 北京大学

项目金额： 18万元

中文摘要： 既往研究表明内源性硫化氢可通过抑制血管平滑肌细胞（VSMC）增殖发挥抗高血压作用，但是硫化氢抑制VSMC增殖的机制尚未完全阐明。本课题将从SirT1/FOXO1通路切入，探索硫化氢对VSMC增殖的抑制机制。首先在自发性高血压大鼠及内皮素-1诱导VSMC模型上，通过补充硫化氢供体及过表达胱硫醚r裂解酶上调内源性硫化氢水平，研究硫化氢对高血压发生中VSMC SirT1/FOXO1通路及VSMC增殖的影响；进一步抑制SirT1活性或表达，研究SirT1/FOXO1通路在硫化氢抑制VSMC增殖中的作用；结合巯基修饰工具药、巯基化修饰特异性探针及半胱氨酸定点突变，研究硫化氢对VSMC SirT1半胱氨酸巯基的巯基化修饰作用，揭示硫化氢调节SirT1的分子机制。通过上述结果，以期阐明硫化氢抑制血管平滑肌细胞异常增殖的分子机制，进一步深化高血压的发病机制。

中文关键词： 硫化氢；血管平滑肌细胞；增殖；SirT1；巯基

英文摘要： It was reported that endogenous hydrogen sulfide played antihypertensive effect via inhibiting the abnormal proliferation of vascular smooth muscle cell (VSMC). However, the mechanism by which hydrogen sulfide inhibits VSMC proliferation has not been clear. In the present study, the applicant plans to explore the mechanisms by which hydrogen sulfide inhibits the VSMC proliferation, targeting on the SirT1/FOXO1 pathway. Firstly, based on the spontaneously hypertensive rats and ET-1-induced rat VSMCs, we are to treat the rats with hydrogen sulfide donor or overexpress cystathionine gamma lyase in VSMC to study the effect of hydrogen sulfide on the VSMC SirT1/FOXO1 pathway and proliferation during the development of hypertension. Secondly, we plan to explore the role of SirT1/FOXO1 pathway in inhibiting VSMC proliferation by hydrogen sulfide via repressing the SirT1 activity or downregulating the SirT1 expression. Finnally, we design to demonstrate the sulfhydration modification by hydrogen sulfide on the thiol group of cysteine in SirT1 with combination of thiol modified drugs, specific probe for sulfhydration modification and site-direct mutation on cysteine in SirT1,and then disclose the molecular mechanism by which hydrogen sulfide acts on the SirT1. The abovementioned studies might be a help to demonstrate the mechanisms by which hydrogen sulfide inhibits the abnormal proliferation of VSMC and deepen the pathogenesis of hypertension.

英文关键词： hydrogen sulfide;vascular smooth muscle cell;proliferation;SirT1;thiol group