Methyltransferase-like 3–catalysed N6-methyladenosine methylation facilitates the contribution of vascular smooth muscle cells to atherosclerosis

Abstract

AIMS: Vascular smooth muscle cells (VSMCs) are involved in the aetiology of atherosclerosis, but whether methyltransferase-like 3 (METTL3)-catalysed N6-methyladenosine (m6A) modulates the contribution of VSMCs to atherosclerosis remains elusive. METHODS AND RESULTS: We generated tamoxifen-inducible VSMC-specific METTL3 knockout mice with VSMC lineage tracing and found that VSMC-specific METTL3 deficiency substantially attenuated atherosclerosis and reduced the proportion of VSMCs in plaques, due to the inhibition of VSMC atheroprone phenotype as characterized by macrophage-like and inflammatory features as well as high migratory and proliferative capacity. m6A-methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with polysome profiling analysis mechanistically displayed METTL3-catalysed m6A methylation of myocardin-related transcription factor A (MRTFA) mRNA and further enhanced YTH N6-methyladenosine RNA-binding protein F3 (YTHDF3)-dependent MRTFA mRNA translation. Conversely, adenovirus or adeno-associated virus-mediated VSMC-specific MRTFA overexpression abolished METTL3 deficiency-mediated alleviation of VSMC atheroprone phenotypic switching and atherosclerotic progression both in vitro and in vivo. CONCLUSION: METTL3 facilitated the contribution of VSMCs to atherosclerosis through the m6A-YTHDF3-dependent MRTFA mRNA translation enhancement.