本课题组前期研究发现心血管系统存在内源性二氧化硫(SO2)生成体系，且具有重要心血管效应，提出"内源性SO2是心血管调节的新型气体信号分子"。然而，内源性SO2的心血管调节机制亟待阐明。本课题将以血管平滑肌细胞(VSMC) 增殖调控为切入点，以可溶性腺苷酸环化酶(sAC)为靶点，探索内源性SO2心血管效应的分子机制。首先研究VSMC增殖调控中SO2对sAC表达及活性的调节作用；通过抑制sAC活性的干预，揭示sAC介导SO2对VSMC增殖的抑制作用；以sAC巯基为靶点，结合巯基修饰剂，揭示SO2激活sAC的分子机制，以期阐明sAC是内源性SO2抑制VSMC增殖的重要分子靶点。研究结果对于发现SO2的心血管效应机制，探索内源性SO2新的生物学效应和分子靶点具有重要科学价值。

Previous study by the applicant team showed that endogenous SO2 pathway was present in cardiovascular tissues and exerted important cardiovascular function. Therefore, the applicant team put forward a concept that SO2 was a novel gasotransmitter in cardiovascular system. However, the mechanisms for its cardiovascular effects need to be clarified. The present study is designed to probe into the molecular target of endogenous SO2 in vascular smooth muscle cell (VSMC) proliferation, targeting on the soluble adenylyl cyclase (sAC). First, the applicant plans to explore the effect of SO2 on the sAC and cAMPin the regulation of VSMC proliferation. Secondly, the applicant plans to discover the significance of sAC in the inhibition of VSMC proliferation by endogenous SO2 through inhibiting sAC activities. Lastly, targeting on the thiol group of sAC, it is designed to examine the molecular mechanism by which SO2 activates sAC by utilizing the thiol-modified drugs. Through the abovementioned studies, the present study would discover sAC as an important target of endogenous SO2, which would be of great scientific significance of exploring the its cardiovascular effect and mechanisms, and novel biological effects and the molecular target of endogenous SO2.

本项目顺利进展，发现过表达内源性二氧化硫（SO2)生成关键酶天冬氨酸氨基转移酶（AAT）抑制血管平滑肌细胞增殖，sAC抑制剂可阻断SO2对增殖的抑制作用，反之敲低AAT促进血管平滑肌细胞增殖；过表达AAT促进血管平滑肌细胞cAMP生成；进一步研究表明SO2可对AC蛋白进行次磺化修饰。上述结果提示，SO2可能通过对AC蛋白的次磺化修饰，激活AC/cAMP通路，进而抑制血管平滑肌细胞增殖。围绕上述研究，共发表SCI论文2篇，培养博士研究生2名，培养中组部万人计划“青年拔尖”人才1人。