TY -的T1 -抑制HIF2信号变弱的起始诱导肺动脉高压是JF -欧洲呼吸杂志》乔和J - 10.1183/13993003.00378 -2019欧元六世- 54 - 6 SP - 1900378 AU - Hu成军盟——Poth Jens m . AU -张,回族非盟- Flockton,阿曼达盟——Laux阿雅AU -库马尔,Sushil AU -麦肯,布列塔尼AU - Mouradian, Gary AU - Li, Min AU - Riddle, Suzette AU - Pugliese, Steven C. AU - Brown, R. Dale AU - Wallace, Eli M. AU - Graham, Brian B. AU - Frid, Maria G. AU - Stenmark，库尔特R. Y1 - 2019年12月01日UR - //www.qdcxjkg.com/content/54/6/1900378.abstract N2 -大多数发表的探讨缺氧诱导因子(hif)在缺氧诱导肺动脉高压发展中的作用的研究采用的模型可能不能概括临床背景，包括使用胚胎HIF消融或激活后已存在肺/血管缺陷的动物。此外，HIF信号如何以及何时有助于低氧诱导的肺动脉高压等关键问题仍未得到解答。通过诱导基因缺失或药物抑制(反意义寡核苷酸(ASO)和小分子抑制剂)抑制HIF1或HIF2的正常成年啮齿动物暴露于短期(4天)或慢性(4 - 5周)缺氧中。进行了血液动力学研究，对动物实施安乐死，获得肺和心脏进行病理和转录组分析。在体外正常肺血管细胞和小鼠中(使用细胞类型特异性HIF缺失)检测肺动脉高压起始的细胞类型特异性HIF信号。在5周时，小鼠的Hif1a缺失并没有阻止低氧诱导的肺动脉高压。Hif2a整体缺失的小鼠不能在长期缺氧中存活。Hif2a部分缺失或Hif2-ASO(但不是Hif1-ASO)降低了4-5周缺氧小鼠的血管肌肉化，增加肺动脉压力和右心室肥厚。 A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4 days of hypoxia, as well as vessel muscularisation, tenascin C accumulation and pulmonary hypertension development in rats exposed to 5 weeks of hypoxia. In vitro, HIF2 induced a distinct set of genes in normal human pulmonary vascular endothelial cells, mediating inflammation and proliferation of endothelial cells and smooth muscle cells. Endothelial Hif2a knockout prevented hypoxia-induced pulmonary hypertension in mice.Inhibition of HIF2 (but not HIF1) can provide a therapeutic approach to prevent the development of hypoxia-induced pulmonary hypertension. Future studies are needed to investigate the role of HIFs in pulmonary hypertension progression and reversal.Activation of HIF2 by hypoxia initiates vascular cell proliferation and recruitment of inflammatory cells at early stages of PH development through HIF2-dependent transcription of genes involved in these pathways in pulmonary vascular cells http://bit.ly/2lFwTGM ER -