Li Qiong, Xu Zhichao, Gong Qianhui, Chen Liyang, Shen Xiaobing, Chen Xiaowei
School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210018, China.
Antioxidants (Basel). 2025 Jul 8;14(7):835. doi: 10.3390/antiox14070835.
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.
高原肺水肿（HAPE）是一种与高原环境相关的严重病症，其分子机制尚未完全阐明。本研究使用简化代表性亚硫酸氢盐测序（RRBS）和850K DNA甲基化芯片系统分析了HAPE患者和健康对照者的DNA甲基化状态，确定了关键的差异甲基化区域（DMR）。靶向亚硫酸氢盐测序（TBS）显示五个基因，即天青杀素1（AZU1）、生长因子受体结合蛋白7（GRB7）、甘露糖受体C型2（MRC2）、RUNX家族转录因子3（RUNX3）和Sept9（SEPT9）的DMR存在显著异常。使用HAPE患者和正常对照者的外周血白细胞以及大鼠肺组织验证了AZU1的异常表达，表明其在HAPE发病机制中的潜在重要性。为了进一步验证AZU1的功能，我们使用人脐静脉内皮细胞（HUVEC）的低压缺氧损伤模型进行了实验研究。结果表明，在低压缺氧条件下AZU1显著上调。敲低AZU1可减轻急性低压缺氧诱导的HUVEC增殖、血管生成和氧化应激损伤的降低。AZU1通过p38/丝裂原活化蛋白激酶（p38/MAPK）信号通路诱导细胞氧化应激。本研究首次通过p38/MAPK途径阐明了AZU1在HAPE中的机制，为HAPE的分子病理学提供了新的见解，并为未来的诊断和治疗策略奠定了基础。
