单核/巨噬细胞内源性二氧化硫的发现及其对单核/巨噬细胞活化的调节作用及机制

单核/巨噬细胞（Mo/Mφ）活化是高血压血管结构重构形成的关键环节，其调控机制亟待阐明。本课题组前期研究发现内源性二氧化硫（SO2）是血管调节的重要分子，基于此，本项目拟揭示Mo/Mφ存在内源性SO2生成体系，并在血管结构重构模型上研究Mo/Mφ激活过程中内源性SO2的变化规律；采用基因操作上调或下调Mo/Mφ中SO2生成，结合巨噬细胞清除剂，从动物和细胞水平研究内源性SO2对Mo/Mφ活化的调节作用及其在血管结构重构中的意义；针对HIF-1α及糖酵解给予干预，阐明内源性SO2通过抑制HIF-1α介导的糖酵解，抑制Mo/Mφ活化；采用探针标记、质谱分析、点突变技术和巯基还原剂干预，揭示内源性SO2通过次磺化修饰HIF-1α半胱氨酸巯基基团，抑制糖酵解，进而抑制Mo/Mφ活化，拮抗血管结构重构。以期阐明Mo/Mφ内源性SO2拮抗血管结构重构的新机制，为探寻高血压防治的炎症干预靶点提供新思路。

Monocyte/macrophage (Mo/Mφ) activation is the key link of hypertensive vascular structural remodeling, and the regulatory mechanism needs to be clarified. Our previous studies showed that endogenous sulfur dioxide (SO2) was an important molecule of vascular regulation. Based on the above findings, the project is designed to reveal if endogenous SO2 pathway exists in Mo/Mφ and analyze the change of endogenous SO2 in the activation of Mo/Mφ in the model of vascular structural remodeling. Also, the study is aimed to examine the regulatory effect of endogenous SO2 on Mo/Mφ activation and its significance in vascular structural remodeling at animal and cell levels by using gene manipulation to upregulate or downregulate SO2 generation in Mo/Mφ and macrophage scavenger. The project is undertaken to further clarify if endogenous SO2 inhibits Mo/Mφ activation by inhibiting HIF-1α-mediated glycolysis with the intervention of HIF-1α and glycolysis. Furthermore, the study is attempted to reveal if endogenous SO2 sulfenylates the cysteine sulfhydryl group of HIF-1α to inhibit glycolysis and Mo/Mφ activation to attenuate vascular structural remodeling by using probe labeling, mass spectrometry analysis, site-directed mutation technology and the disulfide bond reducing agent intervention. The above studies would greatly help in clarifying the new mechanism by which Mo/Mφ-derived SO2 protects against vascular structural remodeling, and providing a new idea to explore the inflammatory intervention target in the prevention and treatment of hypertension.