Methyltransferase-like 3–catalysed N6-methyladenosine methylation facilitates the contribution of vascular smooth muscle cells to atherosclerosis
Zhigang Dong, Yourong Jin, Yiping Shen, Jiaqi Huang, Jiaai Tan, Qianqian Feng, Ze Gong, Shirong Zhu, Huiyue Chen, Fang Yu, Wei Li, Yiting Jia, Wei Kong, Yi Fu
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.