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Cited by 224Cancer, Hypoxia, and MetabolismNitric Oxide and Endothelin EffectsErythropoietin and Anemia Treatment

Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia

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Sogawa, Kazuhiro, Numayama-Tsuruta, Keiko, Ema, Masatsugu, Abe, Manabu, Abe, Hisaku, Fujii-Kuriyama, Yoshiaki·1998·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.95.13.7368PMC PMC22620
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Abstract

Nitric oxide (NO) is known to have various biologic and pathophysiologic effects on organisms. The molecular mechanisms by which NO exerts harmful effects are unknown, although various O 2 radicals and ions that result from reactivity of NO are presumed to be involved. Here we report that adaptive cellular response controlled by the transcription factor hypoxia-inducible factor 1 (HIF-1) in hypoxia is suppressed by NO. Induction of erythropoietin and glycolytic aldolase A mRNAs in hypoxically cultured Hep3B cells, a human hepatoma cell line, was completely and partially inhibited, respectively, by the addition of sodium nitroprusside (SNP), which spontaneously releases NO. A reporter plasmid carrying four hypoxia-response element sequences connected to the luciferase structural gene was constructed and transfected into Hep3B cells. Inducibly expressed luciferase activity in hypoxia was inhibited by the addition of SNP and two other structurally different NO donors, S -nitroso- l -glutathione and 3-morpholinosydnonimine, giving IC 50 values of 7.8, 211, and 490 μM, respectively. Inhibition by SNP was also observed in Neuro 2A and HeLa cells, indicating that the inhibition was not cell-type-specific. The vascular endothelial growth factor promoter activity that is controlled by HIF-1 was also inhibited by SNP (IC 50 = 6.6 μM). Induction generated by the addition of cobalt ion (this treatment mimics hypoxia) was also inhibited by SNP (IC 50 = 2.5 μM). Increased luciferase activity expressed by cotransfection of effector plasmids for HIF-1α or HIF-1α-like factor in hypoxia was also inhibited by the NO donor. We also showed that the inhibition was performed by blocking an activation step of HIF-1α to a DNA-binding form.

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  • Adam17 and Arg2 proteins affect Hif-1α stability and activity by regulating production of tumor necrosis factor α (TNF-α) and nitric oxide, respectively, whereas Mmp3 has key roles in numerous physiological processes.

    “The Adam17 and Arg2 proteins affect Hif-1α stability and activity by regulating production of tumor necrosis factor α (TNF-α) 31,32 and nitric oxide, respectively 33,34 , whereas Mmp3 has key roles in numerous physiological processes 35 .”

    From The yak genome and adaptation to life at high altitude (2012) · cites this paper as [33]

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Authors
Sogawa, K., Numayama-Tsuruta, K., Ema, M., Abe, M., Abe, H., & Fujii-Kuriyama, Y.
Affiliations
  • Tohoku University (JP)
  • Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-77, Japan
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1998-06-23
Volume
95
Issue
13
Pages
7368-7373
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.95.13.7368
PMC
PMC22620
OpenAlex
W2046905314
Cited by
224
References
51
Citations by year
2026: 1 · 2024: 2 · 2022: 3 · 2021: 11 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 8 · 2012: 3
FWCI
4.06
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
HIF-1, nitric oxide donors, hypoxia, erythropoietin, aldolase A, vascular endothelial growth factor, hypoxia response element, sodium nitroprusside, SIN-1, transcriptional regulation
MeSH terms
Cells, Cultured, DNA, DNA-Binding Proteins, Enzyme Induction, Erythropoietin, Fructose-Bisphosphate Aldolase, Humans, Nitric Oxide, Nitroprusside, Nuclear Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, Transfection, Cell Hypoxia, Helix-Loop-Helix Motifs, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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