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

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.

CommentIn

Cardiovasc Res. 2025 May 6;121(4):526-527. doi: 10.1093/cvr/cvaf036.

COI Statement

Conflict of interest: none declared.

Article info

Journal issue:

Volume: 121
Issue: 4

Doi:

10.1093/cvr/cvaf029

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