The methyltransferase METTL3 regulates endothelial cell proliferation and inflammation via m⁶A RNA...

The imbalance of vascular endothelial cell homeostasis is the key mechanism for the progression of many vascular diseases. RNA modification, particularly N⁶-Methyladenosine (m⁶A), plays important function in numerous biological processes. Nevertheless, the regulatory function of m⁶A RNA methylation in endothelial dysfunction remains insufficiently characterized. In this study, we established that the m⁶A methyltransferase METTL3 is critical for regulating endothelial function. Functionally, depletion of METTL3 results in decreased endothelial cells proliferation, survival and inflammatory response. Conversely, overexpression of METTL3 elicited the opposite effects. Mechanistically, MeRIP-seq identified that METTL3 catalyzed m⁶A modification of TRAF1 mRNA and enhanced TRAF1 translation, thereby up-regulation of TRAF1 protein. Over-expression of TRAF1 successfully rescued the inhibition of proliferation and adhesion of endothelial cells due to METTL3 knockdown. Additionally, m⁶A methylation-mediated TRAF1 expression can be reversed by the demethylase ALKBH5. Knockdown of ALKBH5 upregulated the level of m⁶A and protein level of TRAF1, and also increased endothelial cells adhesion and inflammatory response. Collectively, our findings suggest that METTL3 regulates vascular endothelium homeostasis through TRAF1 m⁶A modification, suggesting that targeting the METTL3-m⁶A-TRAF1 axis may hold therapeutic potential for patients with vascular diseases.