气候变化领域集成服务门户(CCPortal): METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium

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DOI	10.1073/pnas.2025070118
	METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium
	Chien C.-S.; Li J.Y.-S.; Chien Y.; Wang M.-L.; Yarmishyn A.A.; Tsai P.-H.; Juan C.-C.; Nguyen P.; Cheng H.-M.; Huo T.-I.; Chiou S.-H.; Chien S.
发表日期	2021
ISSN	00278424
卷号	118 期号:7
英文摘要	Atherosclerosis is characterized by the plaque formation that restricts intraarterial blood flow. The disturbed blood flow with the associated oscillatory stress (OS) at the arterial curvatures and branch points can trigger endothelial activation and is one of the risk factors of atherosclerosis. Many studies reported the mechanotransduction related to OS and atherogenesis; however, the transcriptional and posttranscriptional regulatory mechanisms of atherosclerosis remain unclear. Herein, we investigated the role of N6-methyladenosine (m6A) RNA methylation in mechanotransduction in endothelial cells (ECs) because of its important role in epitranscriptome regulation. We have identified m6A methyltransferase METTL3 as a responsive hub to hemodynamic forces and atherogenic stimuli in ECs. OS led to an up-regulation of METTL3 expression, accompanied by m6A RNA hypermethylation, increased NF-κB p65 Ser536 phosphorylation, and enhanced monocyte adhesion. Knockdown of METTL3 abrogated this OS-induced m6A RNA hypermethylation and other manifestations, while METTL3 overexpression led to changes resembling the OS effects. RNA-sequencing and m6A-enhanced cross-linking and immunoprecipitation (eCLIP) experiments revealed NLRP1 and KLF4 as two hemodynamics-related downstream targets of METTL3-mediated hypermethylation. The METTL3-mediated RNA hypermethylation up-regulated NLRP1 transcript and down-regulated KLF4 transcript through YTHDF1 and YTHDF2 m6A reader proteins, respectively. In the in vivo atherosclerosis model, partial ligation of the carotid artery led to plaque formation and upregulation of METTL3 and NLRP1, with down-regulation of KLF4; knockdown of METTL3 via repetitive shRNA administration prevented the atherogenic process, NLRP3 up-regulation, and KLF4 down-regulation. Collectively, we have demonstrated that METTL3 serves a central role in the atherogenesis induced by OS and disturbed blood flow. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	N6-methyladeosine RNA methylation \| METTL3 \| shear stress \| atherosclerosis \| oscillatory flow
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180651
作者单位	Innovative Cellular Therapy Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan; Institute of Engineering in Medicine, Department of Bioengineering, University of California San Diego, San diego, CA 92093, United States; Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, 11221, Taiwan; Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, 11217, Taiwan; Center for Evidence-based Medicine, Department of Medical Education, Taipei Veterans General Hospital, Taipei, 11217, Taiwan; Institute of Public Health and Community Medicine Research Center, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan; Genomic Research Center, Academia Sinica, Taipei, 11529, Taiwan;...
推荐引用方式 GB/T 7714	Chien C.-S.,Li J.Y.-S.,Chien Y.,et al. METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium[J],2021,118(7).
APA	Chien C.-S..,Li J.Y.-S..,Chien Y..,Wang M.-L..,Yarmishyn A.A..,...&Chien S..(2021).METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium.Proceedings of the National Academy of Sciences of the United States of America,118(7).
MLA	Chien C.-S.,et al."METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium".Proceedings of the National Academy of Sciences of the United States of America 118.7(2021).