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Reactive oxygen species attenuate nitric-oxide-mediated hypoxia-inducible factor-1alpha stabilization.

Abstract
Tissue hypoxia/ischemia are major pathophysiological determinants. Conditions of decreased oxygen availability provoke accumulation and activation of hypoxia-inducible factor-1 (HIF-1). Recent reports demonstrate a crucial role of HIF-1 for inflammatory events. Regulation of hypoxic responses by the inflammatory mediators nitric oxide (NO) and reactive oxygen species (ROS) is believed to be of pathophysiolgical relevance. It is reported that hypoxic stabilization of HIF-1alpha can be antagonized by NO due to its ability to attenuate mitochondrial electron transport. Likely, the formation of ROS could contribute to this effect. As conflicting results emerged from several studies showing either decreased or increased ROS production during hypoxia, we used experiments mimicking hypoxic intracellular ROS changes by using the redox cycling agent 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), which generates superoxide inside cells. Treatment of A549, HEK293, HepG2, and COS cells with DMNQ resulted in a concentration-dependent raise in ROS which correlated with HIF-1alpha accumulation. By using a HIF-1alpha-von Hippel-Lindau tumor suppressor protein binding assay, we show that ROS produced by DMNQ impaired prolyl hydroxylase activity. When HIF-1alpha is stabilized by NO, low concentrations of DMNQ (<1 microM) revealed no effect, intermediate concentrations of 1 to 40 microM DMNQ attenuated HIF-1alpha accumulation and higher concentrations of DMNQ promoted HIF-1alpha stability. Attenuation of NO-induced HIF-1alpha stability regulation by ROS was mediated by an active proteasomal degradation pathway. In conclusion, we propose that scavenging of NO by ROS and vice versa attenuate HIF-1alpha accumulation in a concentration-dependent manner. This is important to fully elucidate HIF-1alpha regulation under inflammatory conditions.
AuthorsRoman Köhl, Jie Zhou, Bernhard Brüne
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 40 Issue 8 Pg. 1430-42 (Apr 15 2006) ISSN: 0891-5849 [Print] United States
PMID16631533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Extracts
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Naphthoquinones
  • Reactive Oxygen Species
  • Peroxynitrous Acid
  • Nitric Oxide
  • 2,3-dimethoxy-1,4-naphthoquinone
  • Catalase
  • Acetylcysteine
Topics
  • Acetylcysteine (pharmacology)
  • Active Transport, Cell Nucleus
  • Apoptosis (drug effects)
  • Catalase (metabolism)
  • Cell Extracts
  • Cell Line
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Naphthoquinones (pharmacology)
  • Nitric Oxide (metabolism)
  • Peroxynitrous Acid (pharmacology)
  • Protein Biosynthesis
  • Reactive Oxygen Species (metabolism)
  • Time Factors
  • Transcriptional Activation (genetics)

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