PMID- 16631533
OWN - NLM
STAT- MEDLINE
DCOM- 20060609
LR  - 20131121
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 40
IP  - 8
DP  - 2006 Apr 15
TI  - Reactive oxygen species attenuate nitric-oxide-mediated hypoxia-inducible 
      factor-1alpha stabilization.
PG  - 1430-42
AB  - 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.
FAU - Kohl, Roman
AU  - Kohl R
AD  - Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang 
      Goethe-University, Frankfurt, Germany.
FAU - Zhou, Jie
AU  - Zhou J
FAU - Brune, Bernhard
AU  - Brune B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060106
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Cell Extracts)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Naphthoquinones)
RN  - 0 (Reactive Oxygen Species)
RN  - 14691-52-2 (Peroxynitrous Acid)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 6956-96-3 (2,3-dimethoxy-1,4-naphthoquinone)
RN  - EC 1.11.1.6 (Catalase)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/pharmacology
MH  - Active Transport, Cell Nucleus
MH  - Apoptosis/drug effects
MH  - Catalase/metabolism
MH  - Cell Extracts
MH  - Cell Line
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Naphthoquinones/pharmacology
MH  - Nitric Oxide/*metabolism
MH  - Peroxynitrous Acid/pharmacology
MH  - Protein Biosynthesis
MH  - Reactive Oxygen Species/*metabolism
MH  - Time Factors
MH  - Transcriptional Activation/genetics
EDAT- 2006/04/25 09:00
MHDA- 2006/06/10 09:00
CRDT- 2006/04/25 09:00
PHST- 2005/07/19 00:00 [received]
PHST- 2005/12/12 00:00 [revised]
PHST- 2005/12/13 00:00 [accepted]
PHST- 2006/04/25 09:00 [pubmed]
PHST- 2006/06/10 09:00 [medline]
PHST- 2006/04/25 09:00 [entrez]
AID - S0891-5849(05)00749-5 [pii]
AID - 10.1016/j.freeradbiomed.2005.12.012 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2006 Apr 15;40(8):1430-42. doi: 
      10.1016/j.freeradbiomed.2005.12.012. Epub 2006 Jan 6.