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Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems

Record type: Article

Although nitrite (NO(2)(-)) and nitrate (NO(3)(-)) have been considered traditionally inert byproducts of nitric oxide (NO) metabolism, recent studies indicate that NO(2)(-) 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 NO(2)(-) exerts its physiological/pharmacological effects remain incompletely understood. We sought to systematically investigate the fate of NO(2)(-) 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 NO(2)(-) 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 NO(2)(-), without passing through the intermediacy of free NO. Inhibitor and subcellular fractionation studies indicate that NO(2)(-) 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 NO(2)(-)-NO pool in cellular processes such as oxygen-sensing and oxygen-dependent modulation of intermediary metabolism.

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Citation

Feelisch, Martin, Fernandez, Bernadette O., Bryan, Nathan S., 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 The Journal of Biological Chemistry, 283, (49), pp. 33927-33934. (doi:10.1074/jbc.M806654200). (PMID:18835812).

More information

e-pub ahead of print date: 8 October 2008
Published date: 5 December 2008
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337522
URI: http://eprints.soton.ac.uk/id/eprint/337522
ISSN: 0021-9258
PURE UUID: 17f457d3-148d-4afb-bf36-de7d479b94f8
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

Catalogue record

Date deposited: 26 Apr 2012 13:38
Last modified: 18 Jul 2017 06:02

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Contributors

Author: Martin Feelisch ORCID iD
Author: Bernadette O. Fernandez
Author: Nathan S. Bryan
Author: Maria Francisca Garcia-Saura
Author: Selena Bauer
Author: David R. Whitlock
Author: Peter C. Ford
Author: David R. Janero
Author: Juan Rodriguez
Author: Houman Ashrafian

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