METTL3-mediated m6A modification of EGR1 mRNA promotes T2DM vasculopathy

• Published in: Cellular signalling 2024-12, Vol.127, p.111564, Article 111564
• Main Authors: Tao, Meng, Shan, Li, Zhang, Wei, Wei, LiangBing, Guo, MingFei, Fang, ZhaoHui, Zhao, JinDong, Gao, JiaRong
• Format: Article
• Language: English
• Subjects: Endothelial-to-mesenchymal transition (EndMT); Human Umbilical Vein Endothelial Cells (HUVECs); Methyltransferase-like 3 (METTL3); N6-methyladenosine (m6A); Type 2 diabetes vascular lesions
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2024.111564

Vascular endothelial dysfunction is one of the leading causes of developing vascular lesions in Type 2 diabetes mellitus (T2DM). In the development of vascular lesions, when endothelial cells are stimulated by hyperglycemia, inflammation and other external conditions, endothelial cell dysfunction will occur, which promotes endothelial cells to lose its typical phenotype and gain mesenchymal characteristics, with the occurrence of endothelial-to-mesenchymal transition (EndMT). At the same time promote endothelial cell proliferation and migration, induce vascular injury. m6A methylation modification enzyme METTL3 is involved in the development of vascular lesions in T2DM. However, the mechanisms by which METTL3 is involved in T2DM vascular lesions are unclear. In this study, we induced T2DM vascular lesions in human umbilical vein endothelial cells (HUVECs) mimicking high glucose and TNF-α (H + T) levels. The effects of METTL3 on HUVECs EndMT, proliferation and migration have been revealed. Protein expression of endothelial calmodulin (VE-Cadherin) and smooth muscle actin (α-SMA) was visualised by western blot and immunofluorescence techniques to evaluate the occurrence of EndMT. In addition, MeRIP-seq revealed a METTL3-mediated m6A modification profile. MeRIP-qPCR combined with m6A site prediction verified the methylation levels of downstream targets and identified EGR1 as a target of METTL3. Activation of EGR1 successfully rescued EndMT in METTL3-deficient HUVECs. In summary, targeting METTL3 may become an important molecular target for intervention in diabetic vascular lesions. •METTL3 affects EndMT to promote HUVECs proliferation and migration.•METTL3 mediated m6A methylation modification regulates EGR1.•EGR1 reversed the effects of METTL3 siRNA in HUVECs after H + T stimulation.