CSE/H2S体系调控是As的重要干预环节，DNA甲基化修饰可能是CSE基因表达的重要调控方式，但对其知之甚少。我们前期发现DNA去甲基化酶TET2具有保护血管内皮细胞功能的潜在效应，初步证实TET2可调控CSE基因表达。据此，提出“TET2通过去甲化作用调控CSE/H2S体系从而保护血管内皮细胞功能拮抗As”的科学假说。项目将首先构建TET2过表达和TET2低表达的小鼠As模型，在整体水平观察TET2对CSE/H2S体系调控作用及对血管内皮功能和As病变形成的影响；然后，在细胞水平运用基因转染和RNA干扰技术，进一步明确TET2调控CSE/H2S体系改善内皮细胞功能的作用，并从去甲基化修饰的角度阐明TET2调控CSE基因表达的分子机制。本研究将从DNA去甲基化修饰这个新视点揭示CSE/H2S体系的调控机制，同时为阐明TET2在As中的作用提供新的科学依据。

The regulation of CSE/H2S has become an important target for intervention of atherosclerosis. DNA methylation , one of the epigenetic modifications, may regulate the expression of CSE. However, it remains unclear whether altered CSE methylation may play a role in linking CSE-H2S dysregulation and atherosclerosis. Our previous studies showed that DNA demethylase Ten-Eleven-Translocation 2 (TET2) can protect vascular endothelial function and regulate the CSE gene expression. Therefore, we hypothesize that TET2 inhibits atherosclerosis by regulating endogenous CSE/H2S to improve vascular endothelial function, which is achieved by DNA demethylation. To confirm this hypothesis, we first generate TET2 overexpression and downregulation atherosclerosis-prone ApoE-/- mice and observe the role of TET2 regulating CSE/H2S system, improving vascular endothelial function and reducing atherosclerosis at systematic level. Next, in vitro, gene transfection and RNA interference are used to intervene signal molecular and observe the effect of TET2 on attenuating endothelial dysfunction by regulating CSE/H2S system, and explore the possible role of the DNA demethylation in this process. The achievement of project is expected to reveal the regulatory mechanism of CSE/H2S system from DNA demethylation, provide new insight to elucidate the role of TET2 in the pathogenesis of atherosclerosis, which will provide novel targets for the prevention and treatment for atherosclerosis.

CSE/H2S体系调控是As的重要干预环节，DNA甲基化修饰可能是CSE基因表达的重要调控方式，但对其知之甚少。我们前期发现DNA去甲基化酶TET2具有保护血管内皮细胞功能的潜在效应，初步证实TET2可调控CSE基因表达。据此，提出“TET2通过去甲化作用调控CSE/H2S体系从而保护血管内皮细胞功能拮抗As”的科学假说。项目通过构建TET2过表达和TET2低表达的小鼠As模型，在整体水平观察了TET2对CSE/H2S体系调控作用及对血管内皮功能和As病变形成的影响；然后，在细胞水平运用基因转染和RNA干扰技术，进一步探讨了TET2调控CSE/H2S体系改善内皮细胞功能的作用，并从去甲基化修饰的角度揭示TET2调控CSE基因表达的分子机制。我们的结果发现TET2可上调ApoE-/-小鼠主动脉CSE/H2S体系，并使主动脉ICAM-1、VCAM-1表达下调，减少血管内皮功能损伤，减轻小鼠As病变程度；明确TET2可下调ox-LDL处理的HUVECs中ICAM-1和VCAM-1表达，抑制HUVECs与人单核细胞THP-1的黏附，改善了HUVEC细胞功能失调；证实TET2使CSE启动子区域发生去甲基化修饰，上调CSE基因表达，增加H2S生成是TET2 调控CSE/H2S体系的分子机制。项目的研究结果从DNA去甲基化这个新视点揭示内源性CSE/H2S体系的调控机制，并进一步揭示TET2在As发病中的作用，为As的防治提供新的药物作用靶点和干预途径。