Role of nitric oxide in the regulation of HIF-1α expression during hypoxia

Faton H. Agani, Michelle Puchowicz, Juan Carlos Chavez, Paola Pichiule, Joseph Lamanna

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor consisting of HIF-1α and HIF-1β subunits, controls the expression of a large number of genes involved in the regulation of cellular responses to reduced oxygen availability. The oxygen-regulated subunit, HIF-1α, is stabilized in cells exposed to hypoxia. The regulation of hypoxic responses by nitric oxide (NO) is believed to have wide pathophysiological relevance, thus we investigated whether NO affects HIF-1 activation in hypoxic cells. Here we show that NO generated from NO donors prevented HIF-1α hypoxic accumulation in Hep 3B and PC-12 cells. Addition of a glutathione analog or peroxynitrite scavengers prevented the NO-induced inhibition of HIF-1α accumulation in both cell lines. Exposure to NO was associated with inhibition of mitochondrial electron transport and compensatory glycolysis, which maintained normal cellular ATP content. Succinate, a Krebs cycle intermediate and respiratory chain substrate, restored HIF-1α hypoxic induction in the cells, suggesting involvement of mitochondria in regulation of HIF-1α accumulation during hypoxia. Regulation of HIF-1α by NO is an additional important mechanism by which NO might modulate cellular responses to hypoxia in mammalian cells.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume283
Issue number1 52-1
StatePublished - 2002
Externally publishedYes

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Hypoxia-Inducible Factor 1
Nitric Oxide
Cells
Electron Transport
Hypoxia
Oxygen
Mitochondria
Peroxynitrous Acid
Citric Acid Cycle
Nitric Oxide Donors
Succinic Acid
Glycolysis
Glutathione
Transcription Factors
Genes
Adenosine Triphosphate
Chemical activation
Availability

All Science Journal Classification (ASJC) codes

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Role of nitric oxide in the regulation of HIF-1α expression during hypoxia. / Agani, Faton H.; Puchowicz, Michelle; Chavez, Juan Carlos; Pichiule, Paola; Lamanna, Joseph.

In: American Journal of Physiology - Cell Physiology, Vol. 283, No. 1 52-1, 2002.

Research output: Contribution to journalArticle

Agani, Faton H. ; Puchowicz, Michelle ; Chavez, Juan Carlos ; Pichiule, Paola ; Lamanna, Joseph. / Role of nitric oxide in the regulation of HIF-1α expression during hypoxia. In: American Journal of Physiology - Cell Physiology. 2002 ; Vol. 283, No. 1 52-1.
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