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三甲基胺N-氧化物通过N6-甲基氨酸介导途径调节巨细胞极化,加剧人类大动脉间歇细胞炎症

Liming Wen¹, Xiangjie Lin¹, Dongtu Hu¹

¹State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, 510515, Guangzhou, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), 510005, Guangzhou, China.

Atherosclerosis

|February 14, 2025

概括

三甲基胺N-氧化物 (TMAO) 通过对巨细胞的Mettl3进行上调来促进化大动脉病,从而通过m6ARNA甲基化抑制IRAK-M,从而导致炎症. 这项研究阐明了CAVD中TMAO驱动的炎症途径.

科学领域:

心血管生物学心血管生物学
疾病的分子机制.
肠道微生物组和新陈代谢

背景情况:

加性大动脉病 (CAVD) 是由肠道微生物代谢物三甲基胺N氧化物 (TMAO) 促进的.
通过TMAO促进CAVD的精确分子机制在很大程度上是未知的.
这项研究调查了N6-甲基亚丁诺辛 (m6A) RNA甲基化在TMAO介导的大动脉内的炎症过程中的作用.

研究的目的:

阐明TMAO促进大动脉膜炎症的机制.
测试TMAO通过m6ARNA甲基化介导的巨细胞两极化调节炎症的假设.
为了确定TMAO诱导的炎症级联中的关键分子参与者.

主要方法:

在体外研究中,使用TMAO刺激巨细胞以评估Mettl3,IRAK-M表达和极化标志物.
用RNA免疫沉 (RIP) 和RNA衰变试验来探索YTHDF2-IRAK-M mRNA相互作用.
在体内研究中使用Irak-m淘汰赛小鼠来评估IRAK-M在CAVD发展中的作用.

主要成果:

在人类CAVD组织和用TMAO治疗的巨细胞中,Mettl3表达升高,而IRAK-M则降低.
TMAO诱导了M1巨细胞的两极分化,并上调了Mettl3,导致IRAK-M的减少.
IRAK-M被确定为Mettl3的m6A标,其删除在小鼠中加速了大动脉损伤.

结论:

TMAO诱导巨细胞中的Mettl3表达,促进M1极化.
通过抑制IRAK-M,m6A/YTHDF2通路调解了TMAO的促炎作用.
由TMAO激活的巨细胞会加剧人类大动脉间歇细胞 (AVIC) 的炎症.

关键词:

加性大动脉膜疾病伊拉克 - 伊拉克 - 伊拉克 - 伊拉克巨细胞的两极分化这是一种N6-甲基氨酸.三甲基胺N-氧化物

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