Suppression of HIF2 signalling attenuates the initiation of hypoxia-induced pulmonary hypertension.

Autor:	Hu CJ; Dept of Craniofacial Biology, School of Dental Medicine, University of Colorado, Aurora, CO, USA.; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA.; These authors share first authorship.; These authors are joint corresponding authors., Poth JM; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA.; Dept of Anesthesiology and Intensive Care Medicine, University Medical Center, Rheinische Friedrich Wilhelms University of Bonn, Bonn, Germany.; These authors share first authorship., Zhang H; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Flockton A; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Laux A; Dept of Craniofacial Biology, School of Dental Medicine, University of Colorado, Aurora, CO, USA., Kumar S; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., McKeon B; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Mouradian G; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Li M; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Riddle S; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Pugliese SC; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Brown RD; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Wallace EM; Peloton Therapeutics Inc., Dallas, TX, USA., Graham BB; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Frid MG; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA., Stenmark KR; Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Depts of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA kurt.stenmark@ucdenver.edu.; These authors are joint corresponding authors.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2019 Dec 12; Vol. 54 (6). Date of Electronic Publication: 2019 Dec 12 (Print Publication: 2019).
DOI:	10.1183/13993003.00378-2019
Abstrakt:	Most published studies addressing the role of hypoxia inducible factors (HIFs) in hypoxia-induced pulmonary hypertension development employ models that may not recapitulate the clinical setting, including the use of animals with pre-existing lung/vascular defects secondary to embryonic HIF ablation or activation. Furthermore, critical questions including how and when HIF signalling contributes to hypoxia-induced pulmonary hypertension remain unanswered.Normal adult rodents in which global HIF1 or HIF2 was inhibited by inducible gene deletion or pharmacological inhibition (antisense oligonucleotides (ASO) and small molecule inhibitors) were exposed to short-term (4 days) or chronic (4-5 weeks) hypoxia. Haemodynamic studies were performed, the animals euthanised, and lungs and hearts obtained for pathological and transcriptomic analysis. Cell-type-specific HIF signals for pulmonary hypertension initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type-specific HIF deletion).Global Hif1a deletion in mice did not prevent hypoxia-induced pulmonary hypertension at 5 weeks. Mice with global Hif2a deletion did not survive long-term hypoxia. Partial Hif2a deletion or Hif2 -ASO (but not Hif1 -ASO) reduced vessel muscularisation, increases in pulmonary arterial pressures and right ventricular hypertrophy in mice exposed to 4-5 weeks of hypoxia. 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. Competing Interests: Conflict of interest: C-J. Hu has nothing to disclose. Conflict of interest: J.M. Poth has nothing to disclose. Conflict of interest: H. Zhang has nothing to disclose. Conflict of interest: A. Flockton has nothing to disclose. Conflict of interest: A. Laux has nothing to disclose. Conflict of interest: S. Kumar has nothing to disclose. Conflict of interest: B. McKeon has nothing to disclose. Conflict of interest: G. Mouradian has nothing to disclose. Conflict of interest: M. Li has nothing to disclose. Conflict of interest: S. Riddle has nothing to disclose. Conflict of interest: S.C. Pugliese has nothing to disclose. Conflict of interest: R.D. Brown has nothing to disclose. Conflict of interest: E.M. Wallace has a patent “Compositions for Use in Treating Pulmonary Arterial Hypertension” pending to Peloton Therapeutics. Conflict of interest: B.B. Graham reports grants from National Institutes of Health, during the conduct of the study. Conflict of interest: M.G. Frid has nothing to disclose. Conflict of interest: K.R. Stenmark reports personal fees for advisory board or steering committee work from Pfizer, New York, Actelion (Entelligence) and Janssen Research and Development, outside the submitted work. (Copyright ©ERS 2019.)
Databáze:	MEDLINE
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