Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1alpha.
Cells exposed to low oxygen concentrations respond by initiating defense mechanisms, including the stabilization of hypoxia-inducible factor (HIF) 1alpha, a transcription factor that upregulates genes such as those involved in glycolysis and angiogenesis. Nitric oxide and other inhibitors of mitochondrial respiration prevent the stabilization of HIF1alpha during hypoxia. In studies of cultured cells, we show that this effect is a result of an increase in prolyl hydroxylase-dependent degradation of HIF1alpha. With the use of Renilla luciferase to detect intracellular oxygen concentrations, we also demonstrate that, upon inhibition of mitochondrial respiration in hypoxia, oxygen is redistributed toward nonrespiratory oxygen-dependent targets such as prolyl hydroxylases so that they do not register hypoxia. Thus, the signaling consequences of hypoxia may be profoundly modified by nitric oxide.
Hagen
Thilo
T
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
Taylor
Cormac T
CT
Lam
Francis
F
Moncada
Salvador
S
D000975:Antioxidants / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007976:Leupeptins / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008689:Methacrylates; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014226:Triazenes / Q000494:pharmacology
C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007976:Leupeptins; D008689:Methacrylates; D020030:Nitric Oxide Donors; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D014157:Transcription Factors; D014226:Triazenes; D009569:Nitric Oxide; C030517:myxothiazol; D003513:Cycloheximide; D008156:Luciferases; D011393:Procollagen-Proline Dioxygenase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D010100:Oxygen