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J. Biol. Chem., Vol. 283, Issue 49, 33927-33934, December 5, 2008

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Tissue Processing of Nitrite in Hypoxia

AN INTRICATE INTERPLAY OF NITRIC OXIDE-GENERATING AND -SCAVENGING SYSTEMS^*

Martin Feelisch¹, Bernadette O. Fernandez², Nathan S. Bryan², Maria Francisca Garcia-Saura, Selena Bauer, David R. Whitlock^||, Peter C. Ford^**, David R. Janero, Juan Rodriguez, and Houman Ashrafian^¶¶

From the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, the Clinical Sciences Research Institute, University of Warwick, Warwick Medical School, Coventry CV4 7AL, United Kingdom, the ¶Brown Foundation Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, Texas 77030, ^||Nitroceutic LLC, Dover, Massachusetts 02030, the ^**Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, the Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, the Department of Physics, Centenary College of Louisiana, Shreveport, Louisiana 71134, and the ^¶¶Department of Cardiovascular Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom

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

Received for publication, August 27, 2008 , and in revised form, September 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL 69029 (to M. F.) and the Kirschstein National Research Service Award Cardiovascular Training Grant (to B. O. F. and N. S. B.). This work was also supported by the Medical Research Council (MRC Strategic Appointment Scheme, to M. F.), and a Wellcome Trust CVRI Fellowship (to H. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental information, Table S1, and Figs. S1 and S2.

² Both authors contributed equally to this work.

¹ To whom correspondence should be addressed: Clinical Sciences Research Institute, University of Warwick, Warwick Medical School, Gibbet Hill Road, Coventry, CV4 7AL, UK. Tel.: 44-0-2476-528372; Fax: 44-0-2476-150589; E-mail: mf{at}warwick.ac.uk.

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