硫化氢抗As血管重构的新机制：巯基化修饰NFIL3抑制MEST介导的内皮间质转化

硫化氢(H2S)抑制异常剪切应力引起的动脉粥样硬化(As)血管重构，但其调控机制尚未阐明。新近研究发现血管内皮间质转化(EndMT)为剪切应力敏感的生物学过程，参与并促进血管重构。本组前期发现，H2S抑制异常剪切应力诱导的EndMT，下调印记基因MEST表达；生物信息学分析发现MEST特异性抑制因子NFIL3含有3个潜在的巯基化修饰位点。基于此，本项目提出“H2S巯基化修饰并激活NFIL3，下调MEST表达，负性调控异常剪切应力诱导的EndMT和As血管重构”。为证实该假说，拟利用人颈动脉斑块、颈总动脉局部结扎的apoE-/-小鼠As模型以及平行平板流动腔系统，结合CRISPR/Cas9、氨基酸定点突变、质谱分析等技术探讨H2S对NFIL3的巯基化修饰、MEST表达、EndMT的影响及其在异常剪切应力引起的As血管重构中的作用，为As血管重构性病变的发生机制和防治提供新的理论及实验依据。

Hydrogen sulfide (H2S) has been found to inhibit abnormal shear stress- induced atherosclerosis(As)-related vascular remodeling. However, the exact mechanism is not fully elucidated. Recent studies have found that endothelium-to-endothelin transition (EndMT) is a shear stress-sensitive biological process that mediates and promotes vascular remodeling. The previous studies in our group have shown that H2S inhibits abnormal shear stress-induced EndMT and down-regulates expression of imprinted gene MEST. Bioinformatics analysis revealed that the MEST-specific inhibitor NFIL3 has three potential thiolated sites. Based on this, this project proposed that H2S can thiolate and activate NFIL3, down-regulates the expression of MEST, thereby negatively regulates EndMT induced by abnormal shear stress to inhibit As-related vascular remodeling. In order to confirm this hypothesis, human carotid plaque, the apoE-/- mouse model of local carotid artery ligation and parallel plate flow cavity system, as well as some techniques including CRISPR/Cas9, amino acid site-directed mutation, mass spectrometry, etc. will be used to explore the effect of H2S on the thiolation of NFIL3, MEST expression, EndMT as well as the shear stress-induced As vascular remodeling. The project will provide new theoretical and experimental basis for the mechanism and prevention of As-related vascular remodeling.