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Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells.
J Biol Chem. 2000 Jul 14; 275(28):21130-9.JB

Abstract

The O(2) and redox-sensitive transcription factors hypoxia inducible factor-1alpha (HIF-1alpha) and nuclear factor-kappaB (NF-kappaB) are differentially regulated in the alveolar epithelium over fetal to neonatal oxygen tensions. We have used fetal alveolar type II epithelial cells to monitor their regulation in association with redox responsiveness to antioxidant pretreatment in vitro. N-Acetyl-l-cysteine, a glutathione (GSH) precursor and a potent scavenger of reactive oxygen species, induced HIF-1alpha and ameliorated NF-kappaB nuclear abundance and DNA binding activity, respectively, in a dose-dependent manner. Analysis of variations in glutathione homeostasis at ascending DeltapO(2) regimen with N-acetyl-(L)-cysteine reveals increased GSH at the expense of the oxidized form of glutathione (GSSG), thereby shifting GSH/GSSG into reduction equilibrium. Pyrrolidine dithiocarbamate (PDTC), which exerts both antioxidant and pro-oxidant effects, provoked a substantial increase in HIF-1alpha nuclear abundance, with no apparent effect on its activation. PDTC reduced NF-kappaB nuclear abundance and its inhibitory effects on binding activity are dose-dependent. Assessment of glutathione homeostasis with PDTC shows increasing levels of GSSG at the expense of GSH, lowering GSH/GSSG in favor of an oxidative equilibrium. Our results indicate the hypoxic activation of HIF-1alpha and the hyperoxic induction of NF-kappaB in the fetal epithelium is redox-sensitive and, thus, tightly regulated by the GSH/GSSG equilibrium. This highlights glutathione as a key regulatory component for determining genetic responsiveness to oxidant/antioxidant imbalance in normal lung development and pathophysiological conditions.

Authors+Show Affiliations

Oxygen Signaling and Lung Membrane Transport Groups, Center for Research into Human Development, Tayside Institute of Child Health, Faculty of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10801793

Citation

Haddad, J J., et al. "Antioxidant/pro-oxidant Equilibrium Regulates HIF-1alpha and NF-kappa B Redox Sensitivity. Evidence for Inhibition By Glutathione Oxidation in Alveolar Epithelial Cells." The Journal of Biological Chemistry, vol. 275, no. 28, 2000, pp. 21130-9.
Haddad JJ, Olver RE, Land SC. Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells. J Biol Chem. 2000;275(28):21130-9.
Haddad, J. J., Olver, R. E., & Land, S. C. (2000). Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells. The Journal of Biological Chemistry, 275(28), 21130-9.
Haddad JJ, Olver RE, Land SC. Antioxidant/pro-oxidant Equilibrium Regulates HIF-1alpha and NF-kappa B Redox Sensitivity. Evidence for Inhibition By Glutathione Oxidation in Alveolar Epithelial Cells. J Biol Chem. 2000 Jul 14;275(28):21130-9. PubMed PMID: 10801793.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells. AU - Haddad,J J, AU - Olver,R E, AU - Land,S C, PY - 2000/5/10/pubmed PY - 2000/8/19/medline PY - 2000/5/10/entrez SP - 21130 EP - 9 JF - The Journal of biological chemistry JO - J Biol Chem VL - 275 IS - 28 N2 - The O(2) and redox-sensitive transcription factors hypoxia inducible factor-1alpha (HIF-1alpha) and nuclear factor-kappaB (NF-kappaB) are differentially regulated in the alveolar epithelium over fetal to neonatal oxygen tensions. We have used fetal alveolar type II epithelial cells to monitor their regulation in association with redox responsiveness to antioxidant pretreatment in vitro. N-Acetyl-l-cysteine, a glutathione (GSH) precursor and a potent scavenger of reactive oxygen species, induced HIF-1alpha and ameliorated NF-kappaB nuclear abundance and DNA binding activity, respectively, in a dose-dependent manner. Analysis of variations in glutathione homeostasis at ascending DeltapO(2) regimen with N-acetyl-(L)-cysteine reveals increased GSH at the expense of the oxidized form of glutathione (GSSG), thereby shifting GSH/GSSG into reduction equilibrium. Pyrrolidine dithiocarbamate (PDTC), which exerts both antioxidant and pro-oxidant effects, provoked a substantial increase in HIF-1alpha nuclear abundance, with no apparent effect on its activation. PDTC reduced NF-kappaB nuclear abundance and its inhibitory effects on binding activity are dose-dependent. Assessment of glutathione homeostasis with PDTC shows increasing levels of GSSG at the expense of GSH, lowering GSH/GSSG in favor of an oxidative equilibrium. Our results indicate the hypoxic activation of HIF-1alpha and the hyperoxic induction of NF-kappaB in the fetal epithelium is redox-sensitive and, thus, tightly regulated by the GSH/GSSG equilibrium. This highlights glutathione as a key regulatory component for determining genetic responsiveness to oxidant/antioxidant imbalance in normal lung development and pathophysiological conditions. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/10801793/Antioxidant/pro_oxidant_equilibrium_regulates_HIF_1alpha_and_NF_kappa_B_redox_sensitivity__Evidence_for_inhibition_by_glutathione_oxidation_in_alveolar_epithelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)79734-8 DB - PRIME DP - Unbound Medicine ER -