Defect of Adaptation to Hypoxia in Patients With COPD Due to Reduction of Histone Deacetylase 7

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-1 alpha 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% CO2 and 94% N-2) for 24 h, and HIF-1 alpha and HDAC7 protein expression in nuclear extracts were determined by sodium dodecyl sulfate poly acrylamide gel electrophoresis (SDS-PAGE)/Western blotting. Results: HIF-1 alpha 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-1 alpha 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-1 alpha protein in nuclei (r = 0.79, P < .05), and HDA.C7 protein expression was correlated with HIF-1 alpha protein in nuclei (r = 0.46, P < .05). HDAC7 knockdown inhibited hypoxia-induced HIF-1 alpha activity in U937 cells, and HIF-1 alpha nuclear translocation and HIF-1 alpha binding to the VEGF promoter in A549 cells. Conclusions: HDAC7 reduction in COPD causes a defect of HIF-1 alpha induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD. CHEST 2012; 141(5):1233-1242