RNA N(6)-methyladenosine modulates endothelial atherogenic responses to disturbed flow in mice.
RNA N(6)-methyladenosine modulates endothelial atherogenic responses to disturbed flow in mice.
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RNA N6-甲基腺苷调节小鼠内皮动脉粥样硬化反应
DOI：
10.7554/elife.69906
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发表时间：
2022-01-10
期刊：
影响因子：
7.7
通讯作者：
Liang D
中科院分区：
文献类型：
--
作者：
Li B;Zhang T;Liu M;Cui Z;Zhang Y;Liu M;Liu Y;Sun Y;Li M;Tian Y;Yang Y;Jiang H;Liang D
动脉粥样硬化优先发生在动脉粥样硬化的血管系统中，其中人脐静脉内皮细胞暴露于扰动的流动。血流紊乱与血管炎症和病灶分布有关。最近的研究表明，表观遗传调控参与动脉粥样硬化的进展。N6-甲基腺苷（m6 A）是真核生物mRNA最普遍的内部修饰，但其在内皮动脉粥样硬化进展中的功能尚不清楚。在这里，我们表明，m6 A介导的表皮生长因子受体（EGFR）信号通路在EC激活调节动脉粥样硬化的过程。振荡应激（OS）降低了甲基转移酶样3（胃L3），主要的m6 A甲基转移酶的表达。通过m6 A测序和功能研究，我们确定m6 A介导血管病理生理基因EGFR的mRNA衰变，导致EC功能障碍。EGFR 3'非翻译区（3' UTR）的m6 A修饰加速其mRNA降解。EGFR 3 'UTR的双突变消除了胃L3诱导的荧光素酶活性。腺病毒介导的胃L3过表达显著降低了存在OS时的EGFR活化和内皮功能障碍。此外，血小板反应蛋白-1（TSP-1），一种EGFR配体，特异性表达于atheroprone区域，而不受胃L3的影响。通过使用shRNA和AG 1478抑制TSP-1/EGFR轴显著改善动脉粥样硬化形成。总之，我们的研究表明，胃L3通过EGFR mRNA的m6 A依赖性稳定化来抑制内皮动脉粥样硬化的进展，突出了RNA转录组学在动脉粥样硬化调节中的重要作用。
Atherosclerosis preferentially occurs in atheroprone vasculature where human umbilical vein endothelial cells are exposed to disturbed flow. Disturbed flow is associated with vascular inflammation and focal distribution. Recent studies have revealed the involvement of epigenetic regulation in atherosclerosis progression. N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA, but its function in endothelial atherogenic progression remains unclear. Here, we show that m6A mediates the epidermal growth factor receptor (EGFR) signaling pathway during EC activation to regulate the atherosclerotic process. Oscillatory stress (OS) reduced the expression of methyltransferase like 3 (METTL3), the primary m6A methyltransferase. Through m6A sequencing and functional studies, we determined that m6A mediates the mRNA decay of the vascular pathophysiology gene EGFR which leads to EC dysfunction. m6A modification of the EGFR 3’ untranslated regions (3’UTR) accelerated its mRNA degradation. Double mutation of the EGFR 3’UTR abolished METTL3-induced luciferase activity. Adenovirus-mediated METTL3 overexpression significantly reduced EGFR activation and endothelial dysfunction in the presence of OS. Furthermore, thrombospondin-1 (TSP-1), an EGFR ligand, was specifically expressed in atheroprone regions without being affected by METTL3. Inhibition of the TSP-1/EGFR axis by using shRNA and AG1478 significantly ameliorated atherogenesis. Overall, our study revealed that METTL3 alleviates endothelial atherogenic progression through m6A-dependent stabilization of EGFR mRNA, highlighting the important role of RNA transcriptomics in atherosclerosis regulation.