{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:16:52Z","timestamp":1790997412494,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,24]],"date-time":"2022-09-24T00:00:00Z","timestamp":1663977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970302"],"award-info":[{"award-number":["81970302"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["yl2021ms06"],"award-info":[{"award-number":["yl2021ms06"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["yl2020py01"],"award-info":[{"award-number":["yl2020py01"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science Foundation Project of the Yili and Jiangsu Joint Institute of Health","award":["81970302"],"award-info":[{"award-number":["81970302"]}]},{"name":"Science Foundation Project of the Yili and Jiangsu Joint Institute of Health","award":["yl2021ms06"],"award-info":[{"award-number":["yl2021ms06"]}]},{"name":"Science Foundation Project of the Yili and Jiangsu Joint Institute of Health","award":["yl2020py01"],"award-info":[{"award-number":["yl2020py01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Objectives: N6-methylladenosine (m6A) modification has not been fully studied in atherosclerosis. The objectives of this study were to investigate differentially expressed m6A methylated peaks and mRNAs, along with the regulatory role of methyltransferase 3 (METTL3) in pathological processes of atherosclerosis. Methods: The pathological models of human coronary artery smooth muscle cells (HCASMCs) were induced in vitro. The differentially expressed mRNAs and m6A peaks were identified by RNA-Seq and meRIP-Seq. The potential mechanisms were analyzed via bioinformatic assays. Methylases expression was tested by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) in HCASMCs, and by immunohistochemical assays in 40 human coronary arteries. The knockdown of METTL3 expression in cells was performed by siRNA transfection, and cell proliferation and migration were detected after transfection. Results: We identified 5121 m6A peaks and 883 mRNAs that were expressed differentially in the pathological processes of HCASMCs. Bioinformatic analyses showed that the different m6A peaks were associated with cell growth and cell adhesion, and the 883 genes showed that the extracellular matrix and PI3K\/AKT pathway regulate the processes of HCASMCs. Additionally, 10 hub genes and 351 mRNAs with differential methylation and expression levels were found. METTL3 was upregulated in the arteries with atherosclerotic lesions and in the proliferation and migration model of HCASMCs, and pathological processes of HCASMCs could be inhibited by the knockdown of METTL3. The mechanisms behind regulation of migration and proliferation reduced by siMETTL3 are concerned with protein synthesis and energy metabolism. Conclusions: These results revealed a new m6A epigenetic method to regulate the progress of atherosclerosis, which suggest approaches for potential therapeutic interventions that target METTL3 for the prevention and treatment of coronary artery diseases.<\/jats:p>","DOI":"10.3390\/cells11192980","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T21:14:28Z","timestamp":1664140468000},"page":"2980","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Exploration of N6-Methyladenosine Profiles of mRNAs and the Function of METTL3 in Atherosclerosis"],"prefix":"10.3390","volume":"11","author":[{"given":"Yaqing","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5019-0776","authenticated-orcid":false,"given":"Rongli","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Friendship Hospital of Ili Kazakh Autonomous Prefecture\uff0cIli & Jiangsu Joint Institute of Health, Yining 835000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4577-032X","authenticated-orcid":false,"given":"Yahong","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yerbolat","family":"Manafhan","sequence":"additional","affiliation":[{"name":"Department of Hypertension, Yili Friendship Hospital, Stalin Road 92, Yining 835000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzhi","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41392-022-00955-7","article-title":"Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention","volume":"7","author":"Kong","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e016360","DOI":"10.1161\/JAHA.120.016360","article-title":"Legumain in Acute Coronary Syndromes: A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial","volume":"9","author":"Gregersen","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40659-020-00306-2","article-title":"LncRNA HCG11 regulates proliferation and apoptosis of vascular smooth muscle cell through targeting miR-144-3p\/FOXF1 axis in atherosclerosis","volume":"53","author":"Liu","year":"2020","journal-title":"Biol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0021-9150(98)00044-6","article-title":"Cell proliferation in normal and atherosclerotic human aorta: Proliferative splash in lipid-rich lesions","volume":"139","author":"Orekhov","year":"1998","journal-title":"Atherosclerosis"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1161\/01.ATV.0000132401.12275.0c","article-title":"Atherosclerotic plaque smooth muscle cells have a distinct phenotype","volume":"24","author":"Mulvihill","year":"2004","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"607605","DOI":"10.3389\/fphar.2020.607605","article-title":"MOF Regulates TNK2 Transcription Expression to Promote Cell Proliferation in Thyroid Cancer","volume":"11","author":"Li","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.14336\/AD.2019.1126","article-title":"An Updated Review of the Epigenetic Mechanism Underlying the Pathogenesis of Age-related Macular Degeneration","volume":"11","author":"Li","year":"2020","journal-title":"Aging Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s12943-020-01194-6","article-title":"Novel insight into the regulatory roles of diverse RNA modifications: Re-defining the bridge between transcription and translation","volume":"19","author":"Shi","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1158\/0008-5472.CAN-18-2965","article-title":"The Critical Role of RNA m(6)A Methylation in Cancer","volume":"79","author":"Lan","year":"2019","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mongelli, A., Atlante, S., Bachetti, T., Martelli, F., Farsetti, A., and Gaetano, C. (2020). Epigenetic Signaling and RNA Regulation in Cardiovascular Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020509"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s12943-019-1109-9","article-title":"Functions of N6-methyladenosine and its role in cancer","volume":"18","author":"He","year":"2019","journal-title":"Mol. Cancer."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.ymthe.2021.09.016","article-title":"METTL3-m(6)A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease","volume":"30","author":"Peng","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/s41422-018-0040-8","article-title":"Dynamic transcriptomic m(6)A decoration: Writers, erasers, readers and functions in RNA metabolism","volume":"28","author":"Yang","year":"2018","journal-title":"Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nature18298","article-title":"Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex","volume":"534","author":"Wang","year":"2016","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nature20577","article-title":"m(6)A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination","volume":"540","author":"Haussmann","year":"2016","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature12730","article-title":"N6-methyladenosine-dependent regulation of messenger RNA stability","volume":"505","author":"Wang","year":"2014","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nature14281","article-title":"N6-methyladenosine marks primary microRNAs for processing","volume":"519","author":"Lee","year":"2015","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3431","DOI":"10.1158\/0008-5472.CAN-20-4107","article-title":"The Emerging Roles of RNA m(6)A Methylation and Demethylation as Critical Regulators of Tumorigenesis, Drug Sensitivity, and Resistance","volume":"81","author":"Lan","year":"2021","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.freeradbiomed.2021.05.009","article-title":"Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis","volume":"171","author":"Zhou","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"656636","DOI":"10.3389\/fcell.2021.656636","article-title":"LncRNA Landscape of Coronary Atherosclerosis Reveals Differentially Expressed LncRNAs in Proliferation and Migration of Coronary Artery Smooth Muscle Cells","volume":"9","author":"Zhou","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s41577-021-00584-1","article-title":"How the immune system shapes atherosclerosis: Roles of innate and adaptive immunity","volume":"22","author":"Roy","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Jain, M., and Chauhan, A.K. (2022). Role of Integrins in Modulating Smooth Muscle Cell Plasticity and Vascular Remodeling: From Expression to Therapeutic Implications. Cells, 11.","DOI":"10.3390\/cells11040646"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nature11112","article-title":"Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq","volume":"485","author":"Dominissini","year":"2012","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.cell.2012.05.003","article-title":"Comprehensive analysis of mRNA methylation reveals enrichment in 3\u2019 UTRs and near stop codons","volume":"149","author":"Meyer","year":"2012","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.cell.2019.06.013","article-title":"Deciphering the \u201cm(6)A Code\u201d via Antibody-Independent Quantitative Profiling","volume":"178","author":"Edelheit","year":"2019","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1080\/15592294.2020.1834917","article-title":"Comprehensive analysis of transcriptome-wide m(6)A methylome in the anterior capsule of the lens of high myopia patients","volume":"16","author":"Wen","year":"2021","journal-title":"Epigenetics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1167\/iovs.61.10.13","article-title":"Identification and Characterization of N6-Methyladenosine CircRNAs and Methyltransferases in the Lens Epithelium Cells From Age-Related Cataract","volume":"61","author":"Li","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1186\/s12935-020-01554-8","article-title":"Joint analysis of lncRNA m(6)A methylome and lncRNA\/mRNA expression profiles in gastric cancer","volume":"20","author":"Lv","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"793","DOI":"10.2217\/epi-2020-0372","article-title":"Transcriptome-wide N6-methyladenosine methylation landscape of coronary artery disease","volume":"13","author":"Deng","year":"2021","journal-title":"Epigenomics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.stem.2014.09.019","article-title":"m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells","volume":"15","author":"Batista","year":"2014","journal-title":"Cell Stem Cell."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Popova, N.V., and J\u00fccker, M. (2022). The Functional Role of Extracellular Matrix Proteins in Cancer. Cancers, 14.","DOI":"10.3390\/cancers14010238"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"852383","DOI":"10.3389\/fonc.2022.852383","article-title":"PI3K\/Akt\/mTOR Signaling Pathway: Role in Esophageal Squamous Cell Carcinoma, Regulatory Mechanisms and Opportunities for Targeted Therapy","volume":"12","author":"Luo","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"700630","DOI":"10.3389\/fcvm.2021.700630","article-title":"Shexiang Baoxin Pills Inhibited Proliferation and Migration of Human Coronary Artery Smooth Muscle Cells via PI3K\/AKT\/mTOR Pathway","volume":"8","author":"Hua","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41421-018-0019-0","article-title":"VIRMA mediates preferential m(6)A mRNA methylation in 3\u2019UTR and near stop codon and associates with alternative polyadenylation","volume":"4","author":"Yue","year":"2018","journal-title":"Cell Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.molcel.2018.02.015","article-title":"Zc3h13 Regulates Nuclear RNA m(6)A Methylation and Mouse Embryonic Stem Cell Self-Renewal","volume":"69","author":"Wen","year":"2018","journal-title":"Mol. Cell."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/nature19342","article-title":"m(6)A RNA methylation promotes XIST-mediated transcriptional repression","volume":"537","author":"Patil","year":"2016","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1002\/hep.29683","article-title":"RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2","volume":"67","author":"Chen","year":"2018","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/1878-0261.12593","article-title":"Loss of RDM1 enhances hepatocellular carcinoma progression via p53 and Ras\/Raf\/ERK pathways","volume":"14","author":"Chen","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_39","first-page":"13423","article-title":"METTL3 facilitates the progression of hepatocellular carcinoma by modulating the m6A level of USP7","volume":"13","author":"Li","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"119366","DOI":"10.1016\/j.lfs.2021.119366","article-title":"The m(6)A methyltransferase METTL3 promotes hypoxic pulmonary arterial hypertension","volume":"274","author":"Qin","year":"2021","journal-title":"Life Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/2980\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:38:54Z","timestamp":1760143134000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/2980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,24]]},"references-count":40,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["cells11192980"],"URL":"https:\/\/doi.org\/10.3390\/cells11192980","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,24]]}}}