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Originally published In Press as doi:10.1074/jbc.M001802200 on September 18, 2000

J. Biol. Chem., Vol. 275, Issue 49, 38239-38244, December 8, 2000
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Catalytic Consumption of Nitric Oxide by Prostaglandin H Synthase-1 Regulates Platelet Function*

Valerie B. O'DonnellDagger §, Barbara ColesDagger , Malcolm J. LewisDagger , Brenda C. Crews, Lawrence J. Marnett, and Bruce A. Freeman||

From the Dagger  Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, United Kingdom, the  Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, and the || Departments of Anesthesiology, Biochemistry and Molecular Genetics, and the Center for Free Radical Biology, University of Alabama, Birmingham, Alabama 35233

Nitric oxide (·NO) plays a central role in vascular homeostasis via regulation of smooth muscle relaxation and platelet aggregation. Although mechanisms for ·NO formation are well known, removal pathways are less well characterized, particularly in cells that respond to ·NO through activation of soluble guanylate cyclase. Herein, we report that ·NO is catalytically consumed by prostaglandin H synthase-1 (PGHS-1) through acting as a reducing peroxidase substrate. With purified ovine PGHS-1, ·NO consumption requires peroxide (LOOH or H2O2), with a Km (app) for 15(S)hydroperoxyeicosatetraenoic acid (HPETE) of 3.27 ± 0.35 µM. During this, 2 mol ·NO are consumed per mol HPETE, and loss of HPETE hydroperoxy group occurs with retention of the conjugated diene spectrum. Hydroperoxide-stimulated ·NO consumption requires heme incorporation, is not inhibited by indomethacin, and is further stimulated by the reducing peroxidase substrate, phenol. PGHS-1-dependent ·NO consumption also occurs during arachidonate, thrombin, or A23187 activation of platelets (1-2 µM·min-1 for typical plasma platelet concentrations) and prevents ·NO stimulation of platelet soluble guanylate cyclase. Platelet sensitivity to ·NO as an inhibitor of aggregation is greater using a platelet-activating stimulus (U46619) that does not cause ·NO consumption, indicating that this mechanism overcomes the anti-aggregatory effects of ·NO. Catalytic consumption of ·NO during eicosanoid synthesis thus represents both a novel proaggregatory function for PGHS-1 and a regulated mechanism for vascular ·NO removal.

* This work was supported by funds from the British Heart Foundation (to M. J. L. and V. B. O.) and National Institutes of Health Grants RO1-HL64937, RO1-HL58115, and P6-HL58418 (to B. A. F.) and CA47479 (to L. J. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Wellcome Trust Research Career Development Fellow. To whom correspondence should be addressed: Wales Heart Research Inst., University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK. Tel.: 44-2920-742058, Fax: 44-2920-747484; E-mail: o- donnellvb@cardiff.ac.uk.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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