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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.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2000 Jul 14; Vol. 275 (28), pp. 21130-9. - Publication Year :
- 2000
-
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.
- Subjects :
- Acetylcysteine pharmacology
Animals
Antioxidants pharmacology
Cell Nucleus metabolism
Cells, Cultured
Fetus
Gene Expression Regulation
Homeostasis
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Kinetics
Oxidants pharmacology
Oxidation-Reduction
Pyrrolidines pharmacology
Rats
Thiocarbamates pharmacology
Transcription Factors
DNA-Binding Proteins metabolism
Glutathione metabolism
Glutathione Disulfide metabolism
NF-kappa B metabolism
Nuclear Proteins metabolism
Pulmonary Alveoli metabolism
Respiratory Mucosa metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 275
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 10801793
- Full Text :
- https://doi.org/10.1074/jbc.M000737200