{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:29:25Z","timestamp":1789576165823,"version":"build-2803163510"},"reference-count":28,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Fund for Colleges and Universities of Jiangsu Province","award":["24KJB360014"],"award-info":[{"award-number":["24KJB360014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38\/mitogen-activated protein kinase (p38\/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38\/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies.<\/jats:p>","DOI":"10.3390\/antiox14070835","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T09:12:48Z","timestamp":1751965968000},"page":"835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["AZU1 as a DNA Methylation-Driven Gene: Promoting Oxidative Stress in High-Altitude Pulmonary Edema"],"prefix":"10.3390","volume":"14","author":[{"given":"Qiong","family":"Li","sequence":"first","affiliation":[{"name":"School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianhui","family":"Gong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobing","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Elderly Care Services and Management, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.7326\/0003-4819-145-7-200610030-00007","article-title":"Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: A randomized trial","volume":"145","author":"Maggiorini","year":"2006","journal-title":"Ann. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/jtm.12017","article-title":"Hypoxia-related altitude illnesses","volume":"20","author":"Netzer","year":"2013","journal-title":"J. Travel Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1164\/rccm.202108-1907OC","article-title":"Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis","volume":"206","author":"Lee","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00018-002-8420-z","article-title":"DNA methylation and the regulation of gene transcription","volume":"59","author":"Attwood","year":"2002","journal-title":"Cell Mol. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1007\/s11427-022-2284-8","article-title":"Genome-wide DNA methylation landscape of four Chinese populations and epigenetic variation linked to Tibetan high-altitude adaptation","volume":"66","author":"Lin","year":"2023","journal-title":"Sci. China Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13148-022-01338-z","article-title":"Differential methylation in EGLN1 associates with blood oxygen saturation and plasma protein levels in high-altitude pulmonary edema","volume":"14","author":"Sharma","year":"2022","journal-title":"Clin. Epigenet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"118873","DOI":"10.1016\/j.lfs.2020.118873","article-title":"VHL gene methylation contributes to excessive erythrocytosis in chronic mountain sickness rat model by upregulating the HIF-2alpha\/EPO pathway","volume":"266","author":"Yang","year":"2021","journal-title":"Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6134","DOI":"10.1073\/pnas.1422759112","article-title":"Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema","volume":"112","author":"Mishra","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xu, Z., Li, Q., and Shen, X. (2023). AZU1 (HBP\/CAP37) and PRKCG (PKC-gamma) may be candidate genes affecting the severity of acute mountain sickness. BMC Med. Genom., 16.","DOI":"10.1186\/s12920-023-01457-3"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1182\/blood-2008-02-139634","article-title":"Neutrophil secretion products pave the way for inflammatory monocytes","volume":"112","author":"Soehnlein","year":"2008","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/nm.4109","article-title":"Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective","volume":"22","author":"Cherepanova","year":"2016","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/joim.12604","article-title":"Heparin-binding protein: A key player in the pathophysiology of organ dysfunction in sepsis","volume":"281","author":"Fisher","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_14","first-page":"53","article-title":"AZU1: A new promising marker for infection in orthopedic and trauma patients?","volume":"23","author":"Hemmann","year":"2024","journal-title":"EXCLI J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R155","DOI":"10.1186\/cc12834","article-title":"Increased plasma levels of heparin-binding protein in patients with acute respiratory distress syndrome","volume":"17","author":"Lin","year":"2013","journal-title":"Crit. Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/jbmr.2446","article-title":"Obstructive sleep apnea and metabolic bone disease: Insights into the relationship between bone and sleep","volume":"30","author":"Swanson","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dougherty, J.A., Patel, N., Kumar, N., Rao, S.G., Angelos, M.G., Singh, H., Cai, C., and Khan, M. (2020). Human Cardiac Progenitor Cells Enhance Exosome Release and Promote Angiogenesis Under Physoxia. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00130"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.redox.2017.02.014","article-title":"Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain","volume":"12","author":"Alva","year":"2017","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.2147\/DDDT.S165695","article-title":"Effects of hydroxyethyl starch 130\/0.4 on the kidney tissue of rats with ureteral obstruction","volume":"12","author":"Gunes","year":"2018","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1111\/j.1471-4159.2009.06096.x","article-title":"Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice","volume":"109","author":"Prada","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1074\/jbc.271.6.2935","article-title":"Identification of defensin-1, defensin-2, and CAP37\/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils","volume":"271","author":"Chertov","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e22580","DOI":"10.1096\/fj.202200228RRRRR","article-title":"Transforming growth factor-beta receptor type 2 is required for heparin-binding protein-induced acute lung injury and vascular leakage for transforming growth factor-beta\/Smad\/Rho signaling pathway activation","volume":"36","author":"Liu","year":"2022","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/j.1476-5381.2012.01827.x","article-title":"Endothelial actions of atrial and B-type natriuretic peptides","volume":"166","author":"Kuhn","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/SHK.0000000000000862","article-title":"Heparin-Binding Protein (HBP): A Causative Marker and Potential Target for Heparin Treatment of Human Sepsis-Induced Acute Kidney Injury","volume":"48","author":"Fisher","year":"2017","journal-title":"Shock"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.7150\/jca.16010","article-title":"Nucleophosmin Mutations Induce Chemosensitivity in THP-1 Leukemia Cells by Suppressing NF-kappaB Activity and Regulating Bax\/Bcl-2 Expression","volume":"7","author":"Zhang","year":"2016","journal-title":"J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.ygyno.2020.08.030","article-title":"mRNA expression in low grade serous ovarian cancer: Results of a nanoString assay in a diverse population","volume":"159","author":"Jordan","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7329","DOI":"10.1038\/s41388-019-0945-9","article-title":"MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma","volume":"38","author":"Berggren","year":"2019","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nakano, R., Kitanaka, T., Namba, S., Kitanaka, N., Suwabe, Y., Konno, T., Yamazaki, J., Nakayama, T., and Sugiya, H. (2020). Non-Transcriptional and Translational Function of Canonical NF-kappaB Signaling in Activating ERK1\/2 in IL-1beta-Induced COX-2 Expression in Synovial Fibroblasts. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.579266"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/7\/835\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:06:25Z","timestamp":1760033185000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/7\/835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["antiox14070835"],"URL":"https:\/\/doi.org\/10.3390\/antiox14070835","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,8]]}}}