Feelisch, Martin, Fernandez, Bernadette O., Bryan, Nathan S., 1973-, Garcia-Saura, Maria Francisca, Bauer, Selena, Whitlock, David R., Ford, Peter C., Janero, David R., Rodriguez, Juan and Ashrafian, Houman. (2008) Tissue processing of nitrite in hypoxia : an intricate interplay of nitric oxide-generating and -scavenging systems. Journal of Biological Chemistry, Vol.283 (No.49). pp. 33927-33934. ISSN 0021-9258

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Abstract

Although nitrite (NO2-) and nitrate (NO3-) have been considered traditionally inert byproducts of nitric oxide (NO) metabolism, recent studies indicate that NO2- represents an important source of NO for processes ranging from angiogenesis through hypoxic vasodilation to ischemic organ protection. Despite intense investigation, the mechanisms through which NO2- exerts its physiological/pharmacological effects remain incompletely understood. We sought to systematically investigate the fate of NO2- in hypoxia from cellular uptake in vitro to tissue utilization in vivo using the Wistar rat as a mammalian model. We find that most tissues (except erythrocytes) produce free NO at rates that are maximal under hypoxia and that correlate robustly with each tissue's capacity for mitochondrial oxygen consumption. By comparing the kinetics of NO release before and after ferricyanide addition in tissue homogenates to mathematical models of NO2- reduction/NO scavenging, we show that the amount of nitrosylated products formed greatly exceeds what can be accounted for by NO trapping. This difference suggests that such products are formed directly from NO2-, without passing through the intermediacy of free NO. Inhibitor and subcellular fractionation studies indicate that NO2- reductase activity involves multiple redundant enzymatic systems (i.e. heme, iron-sulfur cluster, and molybdenum-based reductases) distributed throughout different cellular compartments and acting in concert to elicit NO signaling. These observations hint at conserved roles for the NO2--NO pool in cellular processes such as oxygen-sensing and oxygen-dependent modulation of intermediary metabolism.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology
Divisions:	Faculty of Medicine > Warwick Medical School > Translational & Systems Medicine > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Nitric-oxide synthase, Nitric oxide -- Physiological effect, Anoxemia, Nitrites, Histology
Journal or Publication Title:	Journal of Biological Chemistry
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Official Date:	5 December 2008
Volume:	Vol.283
Number:	No.49
Number of Pages:	8
Page Range:	pp. 33927-33934
Identification Number:	10.1074/jbc.M806654200
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	National Institutes of Health (U.S.) (NIH), Medical Research Council (Great Britain) (MRC), Wellcome Trust (London, England)
Grant number:	HL 69029 (NIH)
URI:	http://wrap.warwick.ac.uk/id/eprint/28975

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