肠道菌群代谢产物氧化三甲胺（TMAO）为新证实的促动脉粥样硬化（As）危险因子，但其作用机制尚未阐明。本项目前期研究表明TMAO上调线粒体功能蛋白SDHB表达，诱导血管内皮细胞（VEC）焦亡并促As；预实验发现，TMAO以及SDHB促VEC线粒体自噬，自噬抑制剂抑制TMAO以及SDHB诱导的VEC焦亡，SDHB过表达导致VEC甘油磷脂代谢紊乱。基于文献以及前期研究，我们提出 “SDHB通过甘油磷脂途径过度激活线粒体自噬，介导TMAO促VEC焦亡和As”的科学假说。为证实该假说，本项目将采用apoE-/-小鼠以及培养的VEC模型探讨并验证SDHB、甘油磷脂代谢、线粒体自噬及焦亡间的关系；再基于代谢组学结果，结合基因转染、HPLC、电镜等方法和技术，从“甘油磷脂代谢-线粒体自噬”角度探讨TMAO促VEC焦亡的调控机制。本研究将进一步拓宽对As发病机制的认识，为有效防治As提供新的思路和靶点。

Intestinal microbial metabolite trimethylamine oxide (TMAO) is a newly proven risk factor for promoting atherosclerosis (As). However, its underlying mechanisms are unclear. Our previous study showed that TMAO induced vascular endothelial cell (VEC) pyroptosis and promoted As by up-regulating the expression of mitochondrial functional protein SDHB. Preliminary experiments found that TMAO and SDHB induced VEC mitophagy, autophagy inhibitors inhibited TMAO and SDHB-induced VEC pyroptosis, and the overexpression of SDHB caused VEC glycerophospholipid metabolism disorder. Based on the literature and previous studies, we propose that "SDHB activates excessive mitophagy through the glycerophospholipid pathway, which mediates TMAO induced VEC pyrolysis and As". To confirm this hypothesis, apoE-/- mice and cultured VEC were used to explore and verify the relationship among SDHB, glycerophospholipid metabolism, mitophagy, and pyroptosis. Based on metabolomics results, gene transfection, HPLC, electron microscopy and other methods and techniques were used to explore the potential mechanisms of TMAO-induced VEC pyrolysis in the way of "glycerophospholipid metabolism-mitophagy". The accomplish of this study will further broaden the understanding of the pathogenesis of As, which might provide new ideas and targets for the effective prevention and treatment of As.