我校原军事医学系高钰琪教授团队在《hypertension》上发表研究成果——EPAS1/SNHG5介导低氧肺血管重塑的表观遗传调控机制及防治研究
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EPAS1/SNHG5介导低氧肺血管重塑的表观遗传调控机制及防治研究

王授衔 陈德伟 高钰琪

低氧性肺动脉高压(Hypoxic Pulmonary Hypertension,HPH) 是高原心脏病和肺源性心脏病发病的中心环节。持续性低氧导致的肺血管是HPH主要的病理生理变化,但具体的机制不清肺血管内皮细胞介导肺血管炎症反应在肺血管重塑中发挥了难以替代的作用。低氧促进内皮细胞中细胞间黏附分子1(intercellular adhesion molecules 1,ICAM1)转录激活是介导白细胞粘附增强的关键事件,白细胞粘附增强可使肺血管形成持续的炎症微环境,促进肺血管重塑并最终导致HPH。缺氧诱导因子2α(又Endothelial PAS domain protein 1,EPAS1)是藏族人群低氧适应的关键基因,EPAS1通过与靶基因启动子区域的低氧反应元件(Hypoxia Response Element, HRE)结合,进而激活靶基因转录。最近研究发现内皮细胞特异敲除EPAS1可显著抑制低氧肺血管重塑及HPH的发生发展,但其机制有待进一步阐明。我们在人原代肺动脉内皮细胞中干扰EPAS1后进行转录组测序分析发现,EPAS1可调控ICAM1的表达。结合生信分析,推测EPAS1可能通过调控ICAM1的转录,促进其表达,增强循环炎症细胞在肺血管聚集并形成促炎微环境,进而促进肺血管重塑

在慢性低氧诱导的HPH小鼠模型中,口服给予EPAS1特异性抑制剂PT2385,结果发现PT2385可以显著降低小鼠右心室压力,并显著改善肺血管重塑,表明EPAS1在低氧肺血管重塑过程中具有重要作用。进一步实验证实,EPAS1可作为转录因子直接增强肺血管内皮细胞中ICAM1的转录,进而介导低氧肺血管重塑从同为第3类肺动脉高压的COPD患者的lncRNA数据和转录测序数据中分析发现,长链非编码RNA SNHG5 (small nucleolar RNA host gene 5)在COPD患者及低氧处理的肺血管内皮细胞中高表达,也可调控内皮细胞中ICMA1的转录。进一步研究表明,EPAS1可通过直接转录激活SNHG5,进而促使SNHG5通过吸附 miR-625-5p解除其对EPAS1的抑制作用,进一步增强EPAS1对ICAM1的转录激活作用。上述研究表明,肺血管内皮细胞中EPAS1在调控ICMA1转录过程中除了直接转录激活外,还可通过EPAS1-SNHG5-miR-625-5p-EPAS1之间形成的环路调节机制来增强ICMA1转录。通过特异性干扰内皮细胞中SNHG5的动物实验也证实SNHG5在低氧性肺血管重塑及HPH中具有重要的调控作用。

上述研究明确了EPAS1介导的肺血管内皮细胞炎症反应是HPH形成的重要机制,并提出了低氧诱导内皮细胞ICAM1转录激活的新机制,也为HPH的发病机制及防治措施研究开辟了新的方向。该研究成果于今年9月发表在《hypertension》杂志上(IF=10.19),陆军军医大学高原军事医学系高钰琪教授和陈德伟副教授为论文通讯作者,博士研究生王授衔为本文的第一作者。

 

附英文摘要

Endothelial PAS domain protein 1(EPAS1), as the major effect gene for the adaptation to chronic hypoxia, is required for hypoxic pulmonary hypertension (HPH). Down-regulated EPAS1 ameliorates the development of HPH. We confirmed that EPAS1 specific inhibitor PT2385 ameliorated HPH features, as demonstrated by right ventricle hypertrophy, right ventricular systolic pressure and pulmonary vascular remodeling. However, the mechanism of EPAS1 in HPH pathogenesis remains unclear. RNA sequencing in human pulmonary artery endothelial cells (HPAECs) with EPAS1 knockdown identified EPAS1-regulated genes, including intercellular adhesion molecules 1 (ICAM1), which created a proinammatory perivascular microenvironment associated with HPH by elevating leukocyte adhesion to the vascular endothelium. Chromatin immunoprecipitation (ChIP) assays revealed that EPAS1 directly bound to ICAM1 promoter. The long non-coding RNA small nucleolar RNA host gene 5 (SNHG5), significantly increased in acute exacerbation period of COPD and hypoxic HPAECs, also contributed to the regulation of ICAM1 expression. Endothelial-specific deletion of Snhg5 also rescued HPH in mice. Over-expression of EPAS1 or SNHG5 enhanced, while the depletion of EPAS1 or SNHG5 attenuated, ICAM1 transactivation. SNHG5 was directly regulated by EPAS1, and interestingly, the upregulated SNHG5 could further enhance the levels of EPAS1 which consequently led to hypoxia-induced ICAM1 transactivation. RNA pull-down assay followed by high-throughput sequencing demonstrated that miR-625-5p could bind to SNHG5. Manipulating miR-625-5p altered the levels of EPAS1 during hypoxia. Our data showed a positive feed-forward exists between EPAS1 and SNHG5 signaling during hypoxia-induced ICAM1transactivation in endothelial cells. Targeting EPAS1 and SNHG5 may provide promising strategies for the prevention of HPH.


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