Role of oxidative stress in intermittent hypoxia-induced immediate early gene activation in rat PC12 cells

Guoxiang Yuan, Gautam Adhikary, Andrew A. McCormick, John Holcroft, Ganesh K. Kumar, Nanduri R. Prabhakar

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

Intermittent hypoxia (IH) occurs in many pathophysiological conditions. The molecular mechanisms associated with IH, however, have received little attention. Previous studies have reported that the c-fos gene via formation of activator protein-1 (AP-1) transcription factor contributes to adaptive responses to continuous hypoxia. In the present study, using a cell culture model we examined whether IH activates c-fos and AP-1 and if so, by what mechanisms. Experiments were performed on rat phaeochromocytoma cells exposed to 21% O2 (normoxia) or 60 and 120 cycles of IH, each cycle consisting 15 s of hypoxia followed by 4 min of normoxia. IH resulted in a significant elevation of c-fos mRNA as well as transcriptional activation. IH was more potent and induced a longer lasting activation of c-fos than comparable cumulative duration of continuous hypoxia. IH increased AP-1 activity and tyrosine hydroxylase (TH) mRNA, an AP-1-regulated downstream gene, and these effects were prevented by antisense c-fos. Superoxide dismutase mimetic, a potent scavenger of superoxide anions, prevented IH-induced c-fos, AP-1 and TH activations. IH increased superoxide anion levels in mitochondria as evidenced by decreased aconitase enzyme activity and increased levels of hydrogen peroxide, a stable dismutated product of superoxide anions. Complex I of the mitochondrial electron transport chain was markedly inhibited in IH exposed cells. Pharmacological inhibitors of complex I mimicked the effects of IH during normoxia and occluded the effects of IH on c-fos activation, suggesting the involvement of the mitochondrial electron transport chain in the generation of superoxide anions during IH. These results suggest IH-induced c-fos-mediated transcriptional activation involves oxidative stress.

Original languageEnglish (US)
Pages (from-to)773-783
Number of pages11
JournalJournal of Physiology
Volume557
Issue number3
DOIs
StatePublished - Jun 15 2004
Externally publishedYes

ASJC Scopus subject areas

  • Physiology

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