RNA N6-methyladenosine modulates endothelial atherogenic responses to disturbed flow in mice
Bochuan Li,
Ting Zhang,
Mengxia Liu,
Zhen Cui,
Yanhong Zhang,
Mingming Liu,
Yanan Liu,
Yongqiao Sun,
Mengqi Li,
Yikui Tian,
Ying Yang,
Hongfeng Jiang,
Degang Liang
Affiliations
Bochuan Li
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
Ting Zhang
CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; China National Center for Bioinformation, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Mengxia Liu
CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; China National Center for Bioinformation, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Zhen Cui
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
Yanhong Zhang
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
Mingming Liu
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
Yanan Liu
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
Yongqiao Sun
CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; China National Center for Bioinformation, Beijing, China
Mengqi Li
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
Yikui Tian
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; China National Center for Bioinformation, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Hongfeng Jiang
Key Laboratory of Remodeling-Related Cardiovascular Diseases (Ministry of Education), Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
Tianjin Key Laboratory of Metabolic Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
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.
