EZH2 inhibition via GSK-126 mitigates EndMT and atherosclerosis in diabetes: A translational epigenetic approach.

While epigenetic regulators are increasingly implicated in atherosclerotic progression, the specific role of Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase, in EndMT in diabetes-associated atherosclerosis remains unclear. We show that EZH2-mediated H3K27 trimethylation is elevated in carotid plaques from diabetic patients and in aortic endothelium of diabetic Apoe-/- mice.

Pharmacologic EZH2 inhibition with GSK-126 attenuated EndMT and reduced atherosclerotic burden in diabetic mice. In human aortic endothelial cells exposed to high glucose/TNF-α or serum from coronary artery disease patients, EZH2 blockade via GSK-126 or shRNA suppressed EndMT and reversed transcriptional programs assessed by RNA sequencing, including COL4A1 and NR2F2. These findings identify EZH2 as a driver of EndMT in diabetes-associated atherosclerosis and highlight EZH2 inhibition as a potential therapeutic strategy to limit vascular pathology.