TET2 expedites coronary heart disease by promoting microRNA-126 expression and inhibiting the E2F3-PI3K-AKT axis.

Abstract

DNA demethylases of the ten-eleven translocation (TET) family serve as tumor suppressors in various human cancers, but their pathogenic effects in coronary heart disease (CHD) remain unclear. Here we report that TET2 is transcriptionally upregulated in CHD patients, where it shows potential as a diagnostic tool. Mechanistic investigations revealed that TET2 facilitates inflammatory responses and cardiomyocyte apoptosis in rats through demethylation of microRNA-126 (miR-126) promoter. This interaction leads to sequestration of miR-126 from its target E2F transcription factor 3 (E2F3), contributing to E2F3 suppression in CHD. Upregulation of miR-126 when TET2 was silenced restored levels of inflammatory factors and aggravated the degree of cardiac injury and cardiomyocyte apoptosis in rats. By contrast, simultaneous overexpression of E2F3 and miR-126 reduced the levels of inflammatory factors, cardiac injury, and cardiomyocyte apoptosis in rats. Also, TET2 was found to regulate the activity of the PI3K-AKT pathway through the miR-126-E2F3 axis. Our findings uncover a novel function for TET2 in facilitating the progression of CHD.