METTL3-catalyzed m6A methylation facilitates the contribution of vascular smooth muscle cells to atherosclerosis

  • Cardiovasc Res. 2025 Feb 20:cvaf029. doi: 10.1093/cvr/cvaf029.
Zhigang Dong  1 ,  Yourong Jin  1 ,  Yicong Shen  1  2 ,  Jiaqi Huang  1 ,  Jiaai Tan  1 ,  Qianqian Feng  1 ,  Ze Gong  1  3 ,  Shirong Zhu  1 ,  Huiyue Chen  1 ,  Fang Yu  1 ,  Wei Li  4 ,  Yiting Jia  1 ,  Wei Kong  1 ,  Yi Fu  1
Affiliations
  • 1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University;  State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
  • 2. Department of Pathophysiology, School of Medicine, Jiangnan University, Wuxi, 214122, China.
  • 3. Hwamei College of Life and Health Sciences, Zhejiang Wanli University, Ningbo 315100, China.
  • 4. Department of Vascular Surgery, Peking University People's Hospital, Peking University, Beijing 100191, China.
PMID: 39977233 DOI: 10.1093/cvr/cvaf029
Abstract

Aims: Vascular smooth muscle cells (VSMCs) are involved in the etiology of atherosclerosis, but whether methyltransferase-like 3 (METTL3)-catalyzed 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 catalyzed 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.

Keywords
RNA methyltransferase METTL3; atherosclerosis; phenotypic switching; vascular smooth muscle cell.
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