EPAS1 (Endothelial PAS Domain Protein 1) Orchestrates Transactivation of Endothelial ICAM1 (Intercellular Adhesion Molecule 1) by Small Nucleolar RNA Host Gene 5 (SNHG5) to Promote Hypoxic Pulmonary Hypertension
EPAS1 (Endothelial PAS Domain Protein 1) Orchestrates Transactivation of Endothelial ICAM1 (Intercellular Adhesion Molecule 1) by Small Nucleolar RNA Host Gene 5 (SNHG5) to Promote Hypoxic Pulmonary Hypertension
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DOI：
10.1161/hypertensionaha.121.16949
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发表时间：
2021-08
期刊：
影响因子：
8.3
通讯作者：
Shouxian Wang;Yu Wang;Chang Liu;Gang Xu;Wen-Xiang Gao;Jiale Hao;Mengjie Zhang;Gang Wu;Yi-dong Yang;Jian Huang;B. Ni;Dewei Chen;Yuqi Gao
中科院分区：
文献类型：
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作者：
Shouxian Wang;Yu Wang;Chang Liu;Gang Xu;Wen-Xiang Gao;Jiale Hao;Mengjie Zhang;Gang Wu;Yi-dong Yang;Jian Huang;B. Ni;Dewei Chen;Yuqi Gao
补充数字内容可在文本中找到。EPAS1（内皮PAS结构域蛋白1）作为慢性缺氧适应的主要作用基因，是低氧性肺动脉高压（HPH）的必需基因。EPAS1下调可改善HPH的发展。我们证实epas1特异性抑制剂PT2385可改善HPH特征，如右心室肥厚、右心室收缩压和肺血管重构。然而，EPAS1在HPH发病中的作用机制尚不清楚。对EPAS1敲低的人肺动脉内皮细胞的RNA测序发现了EPAS1调控基因，包括ICAM1（细胞间粘附分子1），ICAM1通过提高白细胞对血管内皮的粘附，创造了与HPH相关的促炎血管周围微环境。染色质免疫沉淀实验显示EPAS1直接与ICAM1启动子结合。长链非编码RNA小核RNA宿主基因5 （SNHG5）在慢性阻塞性肺疾病急性加重期和缺氧人肺动脉内皮细胞中显著升高，也参与了ICAM1表达的调控。内皮特异性缺失Snhg5也能挽救小鼠的HPH。EPAS1或SNHG5过表达增强，而EPAS1或SNHG5缺失减弱，ICAM1转激活。SNHG5直接受到EPAS1的调控，有趣的是，SNHG5的上调可以进一步提高EPAS1的表达水平，从而导致缺氧诱导的ICAM1转激活。RNA下拉实验和高通量测序表明，miR-625-5p可以结合SNHG5。操纵miR-625-5p改变缺氧期间EPAS1的水平。我们的数据显示，在缺氧诱导的内皮细胞ICAM1转激活过程中，EPAS1和SNHG5信号之间存在正前馈。靶向EPAS1和SNHG5可能为HPH的预防提供有希望的策略。
Supplemental Digital Content is available in the text. EPAS1 (endothelial PAS domain protein 1), as the major effect gene for the adaptation to chronic hypoxia, is required for hypoxic pulmonary hypertension (HPH). Downregulated 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 with EPAS1 knockdown identified EPAS1-regulated genes, including ICAM1 (intercellular adhesion molecule 1), which created a proinflammatory perivascular microenvironment associated with HPH by elevating leukocyte adhesion to the vascular endothelium. Chromatin immunoprecipitation assays revealed that EPAS1 directly bound to ICAM1 promoter. The long noncoding RNA small nucleolar RNA host gene 5 (SNHG5), significantly increased in acute exacerbation period of chronic obstructive pulmonary disease and hypoxic human pulmonary artery endothelial cells, also contributed to the regulation of ICAM1 expression. Endothelial-specific deletion of Snhg5 also rescued HPH in mice. Overexpression 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 ICAM1 transactivation in endothelial cells. Targeting EPAS1 and SNHG5 may provide promising strategies for the prevention of HPH.