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

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.

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。

高同型半胱氨酸血症是动脉粥样硬化的独立危险因子，但通过给予B族维生素和叶酸治疗增加同型半胱氨酸再甲基化而降低高同型半胱氨酸水平却不能有效降低心血管事件的发生。硫化氢是同型半胱氨酸转硫代谢的产物，其本身可以拮抗高同型半胱氨酸的心血管损伤，也可减轻动脉粥样硬化的发生，但其分子机制尚不清楚。本项目发现，硫化氢可以通过硫氢化修饰胱硫醚酶，增加其催化活性，促进同型半胱氨酸的转硫降解从而降低高同型半胱氨酸血症；也可以通过硫氢化SIRT1，增加其去乙酰化活性而减轻内皮细胞炎症、巨噬细胞炎症及胆固醇摄取、肝细胞胆固醇的从头合成；还可以硫氢化PDI，增加其活性，这样也促进蛋白质的折叠，从而减轻高同型半胱氨酸引起的内质网应激反应。本项目阐明可硫化氢分子拮抗高同型半胱氨酸血症及动脉粥样硬化的分子机制，阐明了硫化氢通过蛋白质的硫氢化修饰参与疾病功能调节的新途径，为硫化氢供体临床治疗高同型半胱氨酸血症提供了理论基础。