The inhibitory effect of sodium nitroprusside on HIF-1 activation is not dependent on nitric oxide-soluble guanylyl cyclase pathway.
Adaptation to hypoxia and maintenance of O(2) homeostasis involve a wide range of responses that occur at different organizational levels in the body. One of the most important transcription factors that activate the expression of O(2)-regulated genes is hypoxia-inducible factor 1 (HIF-1). Nitric oxide (NO) mediates a variety of biological effects including relaxation of blood vessels and cytotoxicity of activated macrophages. We investigated the effect of the clinically used nitrates nitroglycerin (NTG), isosorbide dinitrate (ISDN), and sodium nitroprusside (SNP) on HIF-1-mediated transcriptional responses to hypoxia. We demonstrate that among the three nitrates, only SNP inhibits HIF-1 activation in response to hypoxia. In contrast, NTG or ISDN does not affect HIF-1 activity. SNP inhibits the accumulation of HIF-1alpha, the regulatory subunit of HIF-1, and the transcriptional activation of HIF-1alpha via a mechanism that is not dependent on either NO or soluble guanylate cyclase.
Department of Anesthesia, The Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan.
Satoshi
S
Takabuchi
Kiichi
K
Hirota
Kenichiro
K
Nishi
Seiko
S
Oda
Tomoyuki
T
Oda
Koh
K
Shingu
Arimichi
A
Takabayashi
Takehiko
T
Adachi
Gregg L
GL
Semenza
Kazuhiko
K
Fukuda
D000818:Animals; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology*; D005996:Nitroglycerin / Q000378:metabolism; D009599:Nitroprusside / Q000378:metabolism / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014665:Vasodilator Agents / Q000378:metabolism
D003497:Cyclic N-Oxides; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D020030:Nitric Oxide Donors; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014665:Vasodilator Agents; D009599:Nitroprusside; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate; D010100:Oxygen