Format

Send to

Choose Destination
See comment in PubMed Commons below
Chest. 2012 May;141(5):1233-1242. doi: 10.1378/chest.11-1536. Epub 2011 Dec 15.

Defect of adaptation to hypoxia in patients with COPD due to reduction of histone deacetylase 7.

Author information

1
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.
2
Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England.
3
Department of Laboratory Medicine, Dokkyo Medical University Koshigaya Hospital, Koshigaya-City, Saitama, Japan.
4
Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England. Electronic address: k.ito@imperial.ac.uk.

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.

PMID:
22172637
PMCID:
PMC3342783
DOI:
10.1378/chest.11-1536
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center