硫化氢拮抗高同型半胱氨酸诱导的动脉粥样硬化的蛋白质亚硝基化/硫氢化修饰机制

项目名称： 硫化氢拮抗高同型半胱氨酸诱导的动脉粥样硬化的蛋白质亚硝基化/硫氢化修饰机制

项目编号： No.81470552

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 耿彬

作者单位： 北京大学

项目金额： 73万元

中文摘要： 高同型半胱氨酸（Hcy）血症是动脉粥样硬化发病的独立危险因子，临床研究证实给予维生素促进Hcy再甲基化不能减轻心血管损害。那么，增加Hcy转硫代谢生成硫化氢是否能防治心血管损害及其机制尚未阐明。在我们前期工作发现硫化氢降低Hcy并抑制Hcy诱导的心肌氧化应激及内质网应激基础上，结合蛋白质同一半胱氨酸残基可发生亚硝基化/硫氢化修饰以及硫化氢理化特性，提出硫化氢可能通过调节蛋白质半胱氨酸硫氢化修饰，拮抗同型半胱氨酸引起的亚硝基化进而抑制Hcy诱导的损伤。本项目拟以Hcy转硫代谢关键酶-胱硫醚γ裂解酶、蛋白质二硫键异构酶、热休克蛋白27的亚硝基化/硫氢化修饰为靶点，探讨Hcy及硫化氢通过蛋白质亚硝基化/硫氢化修饰参与动脉粥样硬化发病过程中,Hcy的转硫代谢机制、内质网应激机制和炎症机制。本项目可能阐明蛋白质亚硝基化/硫氢化修饰是硫化氢拮抗Hcy诱导的动脉粥样硬化的重要病理生理分子机制。

中文关键词： 动脉粥样硬化；同型半胱氨酸；硫化氢；亚硝基化；硫氢化

英文摘要： Hyperhomocysteinemia is an independent risk factor of atherosclerosis. Folic acid and B vitamins, required for remethylation of homocysteine (Hcy) to methionine, are the most important dietary determinants of homocysteinemia and daily supplementation typically lowers plasma homocysteine levels. Recently, large-scale intervention trials found that combined treatment with folate and vitamin B12, with or without vitamin B6, did not decrease cardiovascular risk in healthy subjects or improve survival in patients with coronary heart disease in spite of adequate homocysteine lowering. Our previous work found that hydrogen sulfide (H2S)-a metabolic production of homocysteine by transsulfide pathway, lowered plasma tHcy, reduced oxidative stress and ER stress. However, the molecular mechanism is still unclear. Based on these findings, this project focus on the S-nitrosylation/sulfhydration of cystathionine gamma lyase to explore the possible regulation on Hcy metabolism; the S-nitrosylation/sulfhydration of protein disulfide isomerase to explore the role of H2S in ER stress; the S-nitrosylation/sulfhydration of heat shock protein 27 to inhibit inflammation by NF-kappa B pathway; thus to investigate the role of H2S in atherosclerosis association with hyperhomocysteinemia. The present study might found a common mechanism of H2S antagonist atherosclerosis association with hyperhomocysteinemia. This project also offer a novel target of drug design for treatment hyperhomocysteinemia.

英文关键词： Atherosclerosis;homocysteinine;hydrogen sulfide;S-nitrosylation;Sulfhydration