NAT10 promotes vascular remodelling via mRNA ac4C acetylation

作者：Yu Cheng, Yue Chen, Hao Luo, Weihong Lin, Xin Lin, Qiong Jiang, Hongjin Liu, Wenkun Liu, Jing Yang, Yu Huang, Jun Fang, Duofen He, Yu Han, Shuo Zheng, Hongmei Ren, Xuewei Xia, Junyi Yu, Lianglong Chen, Chunyu Zeng · 发表于：European Heart Journal · 年份：2024 · DOI：10.1093/eurheartj/ehae707 · 被引用次数：52 · 研究领域：RNA modifications and cancer、Peptidase Inhibition and Analysis、Cancer-related gene regulation

BACKGROUND AND AIMS: Vascular smooth muscle cell (VSMC) phenotype switching is a pathological hallmark in various cardiovascular diseases. N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) is well conserved in the enzymatic modification of ribonucleic acid (RNA). NAT10-mediated ac4C acetylation is involved in various physiological and pathological processes, including cardiac remodelling. However, the biological functions and underlying regulatory mechanisms of mRNA ac4C modifications in vascular diseases remain elusive. METHODS: By combining in-vitro and in-vivo vascular injury models, NAT10 was identified as a crucial protein involved in the promotion of post-injury neointima formation, as well as VSMC phenotype switching. The potential mechanisms of NAT10 in the vascular neointima formation were clarified by RNA sequence (RNA-seq), acetylated mRNA immunoprecipitation sequence (acRIP-seq), and RNA binding protein immunoprecipitation sequence (RIP-seq). RESULTS: NAT10 and ac4C modifications were upregulated in injured human and rodent arteries. Deletion of NAT10 in VSMCs effectively reduced post-injury neointima formation and VSMC phenotype switching. Further RNA-seq, RIP-seq, and acRIP-seq revealed that NAT10, by its ac4C modification, directly interacts with genes, including integrin-β1 (ITGB1) and collagen type I alpha 2 chain (Col1a2) mRNAs. Taking ITGB1 as one example, it showed that NAT10-mediated ac4C consequently increased ITGB1 mRNA stability and ...