M(6)A methylation-mediated elevation of SM22 alpha inhibits the proliferation and migration of vascular smooth muscle cells and ameliorates intimal hyperplasia in type 2 diabetes mellitus

Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by insulin resistance facilitates intimal hyperplasia of type 2 diabetes mellitus (T2DM) and N6-methyladenosine (m(6)A) methylation modification mediates the VSMC proliferation. This study aimed to reveal the m(6)A methylation modification regulatory mechanism. In this study, m(6)A demethylase FTO was elevated in insulin-treated VSMCs and T2DM mice with intimal injury. Functionally, FTO knockdown elevated m(6)A methylation level and further restrained VSMC proliferation and migration induced by insulin. Mechanistically, FTO knockdown elevated Smooth muscle 22 alpha (SM22 alpha) expression and m(6)A-binding protein IGF2BP2 enhanced SM22 alpha mRNA stability by recognizing and binding to m(6)A methylation modified mRNA. In vivo studies confirmed that the elevated m(6)A modification level of SM22 alpha mRNA mitigated intimal hyperplasia in T2DM mice. Conclusively, m(6)A methylation-mediated elevation of SM22 alpha restrained VSMC proliferation and migration and ameliorated intimal hyperplasia in T2DM.