Regulation of endothelial heme oxygenase activity during hypoxia is dependent on chelatable iron.
The regulation of heme oxygenase (HO) activity and its dependence on iron was studied in bovine aortic endothelial cells (BAEC) subjected to hypoxia-reoxygenation (H/R). HO activity was induced by hypoxia (10 h) and continued to increase during the reoxygenation phase. HO-1 protein levels were strongly induced by hypoxia from undetectable levels and remained elevated at least 8 h postreoxygenation. Addition of the Fe(3+) chelator desferrioxamine mesylate (DFO) or the Fe(2+) chelator o-phenanthroline during hypoxia alone or during the entire H/R period inhibited the induction of HO activity and HO-1 protein levels. However, DFO had no effect and o-phenanthroline had a partial inhibitory effect on HO activity and protein levels when added only during reoxygenation. Loading of BAEC with Fe(3+) enhanced the activation of the HO-1 gene by H/R, whereas loading with L-aminolevulinic acid, which stimulates heme synthesis, had little effect. These results suggest that chelatable iron participates in regulating HO expression during hypoxia.
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Department of Medicine, Southern Illinois University School of Medicine, Springfield, Illinois 62794, USA.
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D000111:Acetylcysteine / Q000494:pharmacology; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002248:Carbon Monoxide / Q000378:metabolism; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D005290:Ferric Compounds / Q000378:metabolism / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D000860:Hypoxia / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010618:Phenanthrolines / Q000494:pharmacology; D017319:Photosensitizing Agents / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000494:pharmacology*
D005290:Ferric Compounds; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D010618:Phenanthrolines; D017319:Photosensitizing Agents; D000644:Quaternary Ammonium Compounds; D002248:Carbon Monoxide; D000622:Aminolevulinic Acid; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D003676:Deferoxamine; C013531:ferric ammonium citrate; C025205:1,10-phenanthroline; D000111:Acetylcysteine