M6A methylation-mediated elevation of SM22α inhibits the proliferation and migration of vascular smooth muscle cells and ameliorates intimal hyperplasia in type 2 diabetes mellitus

Abstract

Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by insulin resistance facilitates intimal hyperplasia of type 2 diabetes mellitus (T2DM) and N6-methyladenosine (m⁶A) methylation modification mediates the VSMC proliferation. This study aimed to reveal the m⁶A methylation modification regulatory mechanism. In this study, m⁶A demethylase FTO was elevated in insulin-treated VSMCs and T2DM mice with intimal injury. Functionally, FTO knockdown elevated m⁶A methylation level and further restrained VSMC proliferation and migration induced by insulin. Mechanistically, FTO knockdown elevated Smooth muscle 22 alpha (SM22α) expression and m⁶A-binding protein IGF2BP2 enhanced SM22α mRNA stability by recognizing and binding to m⁶A methylation modified mRNA. In vivo studies confirmed that the elevated m⁶A modification level of SM22α mRNA mitigated intimal hyperplasia in T2DM mice. Conclusively, m⁶A methylation-mediated elevation of SM22α restrained VSMC proliferation and migration and ameliorated intimal hyperplasia in T2DM.

Keywords: N6-methyladenosine (m6A); Type 2 diabetes mellitus (T2DM); intimal hyperplasia; vascular smooth muscle cells (VSMCs).