TFPI2 hypermethylation promotes diabetic atherosclerosis progression through the Ap2α/PPARγ axis

Diabetes mellitus significantly escalates the risk of accelerated atherosclerosis (AS), severely affecting cardiovascular health. Our research, leveraging Gene Expression Omnibus (GEO) database analysis (GSE118481), revealed diminished TFPI2 expression in diabetic patients' atherosclerotic plaques. Further validation in carotid artery plaques and an AS mouse model confirmed TFPI2's reduced expression in diabetes. Through TFPI2 knockdown in non-diabetic mice, we observed aggravated plaque burden and increased inflammatory M1 macrophage polarization. Conversely, TFPI2 overexpression in diabetic mice improved plaque stability and induced reparative M2 macrophage polarization, countering hyperglycemia's negative effects. Mechanistically, transcription factor activator protein 2α (AP-2α) is a repressor of PPPARg transcription, and the interaction of TFPI2 with the transcription factor AP-2α blocks AP-2α binding to the PPARγ gene promoter, which is essential for PPARγ-mediated transcription and the transition from M1 to M2 macrophages. Additionally, hyperglycemia-induced DNA methyltransferase 1 (DNMT1) upregulation heightens TFPI2 methylation, reducing its expression. Our findings spotlight the TFPI2/AP-2α/PPARγ axis as crucial in diabetic AS modulation, proposing its targeting as a new therapeutic strategy to halt diabetes-driven AS progression, highlighting TFPI2's therapeutic promise in addressing diabetes-related cardiovascular issues.