Dong Zhigang, Jin Yourong, Shen Yicong, Huang Jiaqi, Tan Jiaai, Feng Qianqian, Gong Ze, Zhu Shirong, Chen Huiyue, Yu Fang, Li Wei, Jia Yiting, Kong Wei, Fu Yi
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
Cardiovasc Res. 2025 May 6;121(4):568-584. doi: 10.1093/cvr/cvaf029.
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.
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.
METTL3 facilitated the contribution of VSMCs to atherosclerosis through the m6A-YTHDF3-dependent MRTFA mRNA translation enhancement.
血管平滑肌细胞（VSMC）参与动脉粥样硬化的发病机制，但甲基转移酶样3（METTL3）催化的N6-甲基腺苷（m6A）是否调节VSMC对动脉粥样硬化的作用仍不清楚。
我们构建了他莫昔芬诱导的VSMC特异性METTL3基因敲除小鼠并进行VSMC谱系追踪，发现VSMC特异性METTL3缺乏显著减轻了动脉粥样硬化，并降低了斑块中VSMC的比例，这是由于抑制了具有巨噬细胞样和炎症特征以及高迁移和增殖能力的VSMC易患动脉粥样硬化表型。m6A甲基化RNA免疫沉淀测序（MeRIP-Seq）结合多聚核糖体分析从机制上显示METTL3催化心肌素相关转录因子A（MRTFA）mRNA的m6A甲基化，并进一步增强YTH N6-甲基腺苷RNA结合蛋白F3（YTHDF3）依赖性的MRTFA mRNA翻译。相反，腺病毒或腺相关病毒介导的VSMC特异性MRTFA过表达消除了METTL3缺乏介导的体外和体内VSMC易患动脉粥样硬化表型转换和动脉粥样硬化进展的缓解。
METTL3通过m6A-YTHDF3依赖性增强MRTFA mRNA翻译促进VSMC对动脉粥样硬化的作用。
