RNA N6-methyladenosine modulates endothelial atherogenic responses to disturbed flow in mice
- Tianjin Medical University, China
- Chinese Academy of Sciences, China
- Capital Medical University, China
Abstract
Atherosclerosis preferentially occurs in atheroprone vasculature where human umbilical vein endothelial cells (HUVECs) 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 EGFR signaling pathway during EC activation to regulate the atherosclerotic process. Oscillatory stress (OS) reduced the expression of 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'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, 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.
Data availability
RNA-seq and MeRIP-seq data generated in this study have been deposited to the Genome Sequence Archive in BIG Data Center under accession number PRJCA004746.
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RNA N6-methyladenosine modulates endothelial atherogenic responses to disturbed flowGenome Sequence Archive, PRJCA004746.
Article and author information
Author details
Funding
National Natural Science Foundation of China (81900396)
- Bochuan Li
National Natural Science Foundation of China (82000477)
- Mengqi Li
National Natural Science Foundation of China (81970392)
- Hongfeng Jiang
Postdoctoral Research Foundation of China (2019M661041)
- Bochuan Li
Postdoctoral Research Foundation of China (BX20190235)
- Bochuan Li
China Association for Science and Technology (Excellent Sino-foreign Youth Exchange Program)
- Bochuan Li
National Natural Science Foundation of China (91940304)
- Ying Yang
Chinese Academy of Sciences (2018133)
- Ying Yang
National Key Research and Development Program of China (2018YFA0801200)
- Ying Yang
Beijing Nova Program (Z201100006820104)
- Ying Yang
National Natural Science Foundation of China (81870207)
- Yikui Tian
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The investigation conformed to the Guide for the Care and Use of Laboratory Animals by the US National Institutes of Health (NIH 17 Publication No. 85-23, revised in 2011). All study protocols and the use of animals were approved by the Institutional Animal Care and Use Committee of Tianjin Medical University.
Copyright
© 2022, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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RNA N6-methyladenosine modulates endothelial atherogenic responses to disturbed flow in mice
eLife 11:e69906.
https://doi.org/10.7554/eLife.69906
