METTL3-mediated m6A modification exacerbates vascular endothelial inflammation in coronary artery disease by regulating DNMT1 mRNA stability.

Chronic vascular endothelial inflammation plays a pivotal role in the pathogenesis of coronary artery disease (CAD). N6-methyladenosine (m6A), the predominant epitranscriptomic modification in messenger RNA (mRNA), regulates pro-atherogenic inflammatory responses in coronary endothelial cells. This study explores the role of the m6A methyltransferase METTL3 in CAD-associated endothelial inflammation through its regulation of DNA methyltransferase 1 (DNMT1) mRNA stability. Using cultured human coronary artery endothelial cells (HCAECs), an apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis, and clinical atherosclerotic specimens from CAD patients, a marked increase in METTL3 expression was observed in CAD endothelium and within plaques. METTL3 knockdown strongly suppressed tumor necrosis factor-α (TNF-α)-induced expression of pro-inflammatory mediators interleukin-6 (IL-6) and interleukin-1β (IL-1β), while upregulating anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10). Mechanistically, METTL3 bound to and deposited m6A modifications in the 3' untranslated region (3'UTR) of DNMT1 mRNA, thereby enhancing its association with the m6A reader protein YTH N6-methyladenosine RNA binding protein 1 (YTHDF1). This interaction increased DNMT1 mRNA stability and elevated its protein levels. Furthermore, endothelial-specific Mettl3 deletion significantly reduced aortic atherosclerotic lesion area and inflammatory infiltration in ApoE-/- mice. In summary, METTL3-mediated m6A modification promotes DNMT1 expression by stabilizing its mRNA, thereby aggravating vascular endothelial inflammation in CAD. The METTL3-m6A-DNMT1 axis may represent a potential therapeutic target for CAD.