DNA甲基化参与糖尿病动脉粥样硬化（AS）发生发展，其具体机制和靶点尚未完全阐明。巨噬细胞极化是AS进展的重要病理基础，而PPARγ是其关键调控分子。我们前期研究发现糖尿病患者和小鼠AS斑块中TFPI2启动子高甲基化和低表达，伴随DNMT1上调；过表达TFPI2负向调控AP2α/PPARγ轴，抑制M1型巨噬细胞极化。在此基础上提出如下假说：高糖通过上调DNMT1诱导TFPI2高甲基化，抑制TFPI2/AP2α/PPARγ轴，从而促进M1型巨噬细胞极化和AS进展。本课题拟在颈动脉内膜剥脱术中收集人AS斑块组织，观察TFPI2甲基化与糖尿病AS的关系；建立糖尿病AS小鼠模型并提取小鼠骨髓巨噬细胞，采用基因转染技术及抑制剂调控相关分子的表达，揭示高糖调控TFPI2表达的机制，并阐明TFPI2/AP2α/PPARγ轴在巨噬细胞极化和AS进展中的作用。该课题将为糖尿病AS的治疗提供新靶点和理论依据。

DNA methylation play a substantial role in the development and progression of diabetic atherosclerosis (AS), however, the molecular mechanisms and target genes have not been fully clarified. Macrophage polarization is an important pathologic basis of AS progression, while PPARγ is a key regulatory molecule involved in. Pre-study in our team has found TFPI2 hypermethylation and low expression, as well as DNMT1 upregulation in diabetic AS. Besides, TFPI2 overexpression negatively regulated AP2α/PPARγ axis, inhibiting M1 macrophage polarization. So we present a hypothesis: Hyperglycemia promotes M1 macrophage polarization and AS progression via TFPI2 hypermethylation-induced inactivation of TFPI2/AP2α/PPARγ axis. In this project, we will gather AS plaques from patients undergoing carotid endarterectomy, and observe the relationship between TFPI2 methylation and diabetic AS. We also apply gene transfer technique or inhibitor invention in diabetic AS mice and high glucose-stimulated mouse bone marrow macrophages (BMDMs), clarify the molecular mechanism of hyperglycemia-induced TFPI2 hypermethylation and low expression, and identify the role of TFPI2/AP2α/PPARγ axis in macrophage polarization and AS progression. This study may provide new targets and theoretical basis for the treatment of diabetic AS.