title: Defect of adaptation to hypoxia in patients with COPD due to reduction of histone deacetylase 7.
abstract: BACKGROUND
  Hypoxia inducible factor (HIF)-1 plays an important role in cellular adaptation to hypoxia by activating oxygen-regulated genes such as vascular endothelial growth factor (VEGF) and erythropoietin. Sputum VEGF levels are reported to be decreased in COPD, despite hypoxia. Here we show that patients with COPD fail to induce HIF-1α and VEGF under hypoxic condition because of a reduction in histone deacetylase (HDAC) 7.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were obtained from patients with moderate to severe COPD (n = 21), smokers without COPD (n = 12), and nonsmokers (n = 15). PBMCs were exposed to hypoxia (1% oxygen, 5% CO(2), and 94% N(2)) for 24 h, and HIF-1α and HDAC7 protein expression in nuclear extracts were determined by sodium dodecyl sulfate poly acrylamide gel electrophoresis (SDS-PAGE)/Western blotting.
  
  
  RESULTS
  HIF-1α was significantly induced by hypoxia in each group when compared with the normoxic condition (12-fold induction in nonsmokers, 24-fold induction in smokers without COPD, fourfold induction in COPD), but induction of HIF-1α under hypoxia was significantly lower in patients with COPD than in nonsmokers and smokers without COPD (P < .05 and P < .01, respectively). VEGF messenger RNA detected by quantitative real-time polymerase chain reaction was correlated with HIF-1α protein in nuclei (r = 0.79, P < .05), and HDAC7 protein expression was correlated with HIF-1α protein in nuclei (r = 0.46, P < .05). HDAC7 knockdown inhibited hypoxia-induced HIF-1α activity in U937 cells, and HIF-1α nuclear translocation and HIF-1α binding to the VEGF promoter in A549 cells.
  
  
  CONCLUSIONS
  HDAC7 reduction in COPD causes a defect of HIF-1α induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England; Department of Laboratory Medicine, Dokkyo Medical University Koshigaya Hospital, Koshigaya-City, Saitama, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: To
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamura
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Charron
authors.affiliation: Department of Laboratory Medicine, Dokkyo Medical University Koshigaya Hospital, Koshigaya-City, Saitama, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Haruki
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England. Electronic address: k.ito@imperial.ac.uk.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000368:Aged; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D004921:Erythropoietin / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006655:Histone Deacetylases / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D013223:Statistics as Topic; D015533:Transcriptional Activation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; C543273:HDAC7 protein, human; D006655:Histone Deacetylases