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However, its role in PAH remains elusive. We designed this study to investigate whether m6A modification and its effector proteins play a role in pulmonary vascular resistance. Lung samples were used to profile m6A concentrations in control subjects and patients with PAH. Bioinformatics analysis, real-time PCR, immunohistochemistry, and Western blotting were used to determine the role of m6A effectors in PAH. The biological effects of GRAP modified by m6A were investigated using in vitro and in vivo models. Furthermore, RIP-PCR was used to assess the writers and readers of GRAP. In this study, we revealed that m6A-modified GRAP mRNA was upregulated in PAH lung samples, cHx\/Su-induced mouse models, and hypoxia-stimulated HPASMCs; however, GRAP mRNA and protein were abnormally downregulated. Functionally, overexpression of GRAP drastically alleviated the proliferative and invasive ability of PAH HPASMCs through inhibition of the Ras\/ERK signaling pathway in vitro and in vivo. In addition, METTL14 (methyltransferase-like 14) and the m6A binding protein YTHDF2 were significantly increased in PAH. Moreover, we found that m6A-modified GRAP mRNA was recognized by YTHDF2 to mediate the degradation. GRAP expression was consistently negatively correlated with METTL14 and YTHDF2 in vivo and in vitro. Taken together, for the first time, our findings highlight the function and therapeutic target value of GRAP and extend our understanding of the importance of RNA epigenetics in PAH.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0429oc","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T13:44:16Z","timestamp":1660657456000},"page":"574-588","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":27,"title":["m6A Modification-mediated GRAP Regulates Vascular Remodeling in Hypoxic Pulmonary Hypertension"],"prefix":"10.1093","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1154-2094","authenticated-orcid":false,"given":"Pengfei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cardiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongpu","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Cardiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi, China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Respiration, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzeng","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Cardiology"},{"name":"Department of Cardiology, National Clinical Research Centre for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"2026012204003625200_bib1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1161\/CIRCRESAHA.115.301146","article-title":"Pulmonary arterial hypertension: the clinical syndrome","volume":"115","author":"Lai","year":"2014","journal-title":"Circ Res"},{"key":"2026012204003625200_bib2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.atherosclerosis.2006.01.018","article-title":"Aging, smooth muscle cells and vascular pathobiology: implications for atherosclerosis","volume":"188","author":"Orlandi","year":"2006","journal-title":"Atherosclerosis"},{"key":"2026012204003625200_bib3","doi-asserted-by":"crossref","first-page":"13S","DOI":"10.1016\/j.jacc.2004.02.029","article-title":"Cellular and molecular pathobiology of pulmonary arterial hypertension","volume":"43","author":"Humbert","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"2026012204003625200_bib4","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1165\/rcmb.2009-0389TR","article-title":"Reversible or irreversible remodeling in pulmonary arterial hypertension","volume":"43","author":"Sakao","year":"2010","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012204003625200_bib5","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nrcardio.2017.84","article-title":"Epidemiology and treatment of pulmonary arterial hypertension","volume":"14","author":"Lau","year":"2017","journal-title":"Nat Rev Cardiol"},{"key":"2026012204003625200_bib6","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1183\/13993003.02043-2015","article-title":"Initial dual oral combination therapy in pulmonary arterial hypertension","volume":"47","author":"Sitbon","year":"2016","journal-title":"Eur Respir J"},{"key":"2026012204003625200_bib7","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1164\/rccm.201203-0383OC","article-title":"Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland","volume":"186","author":"Ling","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026012204003625200_bib8","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.pharmthera.2013.10.002","article-title":"Targeted therapies in pulmonary arterial hypertension","volume":"141","author":"Montani","year":"2014","journal-title":"Pharmacol Ther"},{"key":"2026012204003625200_bib9","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1165\/rcmb.v63erratum2","article-title":"Erratum: exploring new therapeutic pathways in pulmonary hypertension. 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