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J. Biol. Chem., Vol. 279, Issue 10, 8820-8826, March 5, 2004

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Pro-thrombotic State Induced by Post-translational Modification of Fibrinogen by Reactive Nitrogen Species^*

Caryn Vadseth, Jose M. Souza, Leonor Thomson, Amy Seagraves, Chandrasekaran Nagaswami, Tomas Scheiner¶, Jim Torbet, Gaston Vilaire||, Joel S. Bennett||, Juan-Carlos Murciano**, Vladimir Muzykantov**, Marc S. Penn, Stanley L. Hazen, John W. Weisel, and Harry Ischiropoulos¶¶

From the Stokes Research Institute and Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia and the University of Pennsylvania, the Department of Cell and Developmental Biology, ^||Hematology-Oncology Division, Department of Medicine, ^**Institute for Environmental Medicine and Department of Pharmacology, the University of Pennsylvania, Philadelphia, Pennsylvania 19104, and the Departments of Cell Biology and Cardiovascular Medicine, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Formation of nitric oxide-derived oxidants has been linked to development of atherosclerosis and associated thrombotic complications. Although systemic levels of protein nitrotyrosine predict risk for coronary artery disease, neither specific proteins targeted for modification nor functional consequences that might contribute to disease pathogenesis have been defined. Here we report a selective increase in circulating levels of nitrated fibrinogen in patients with coronary artery disease. Exposure of fibrinogen to nitrating oxidants, including those produced by the myeloperoxidase-hydrogen peroxide-nitrite system, significantly accelerates clot formation and factor XIII cross-linking, whereas exposure of fibrinogen to non-nitrating oxidants decelerates clot formation. Clots formed with fibrinogen exposed to nitrating oxidants are composed of large bundles made from twisted thin fibrin fibers with increased permeation and a decrease in storage modulus G' value, suggesting that these clots could be easily deformed by mechanical stresses. In contrast, clots formed with fibrinogen exposed to non-nitrating oxidants showed decreased permeation with normal architecture. Fibrinogen modified by exposure to physiologic nitration systems demonstrated no difference in the rate of plasmin-induced clot lysis, platelet aggregation, or binding. Thus, increased levels of fibrinogen nitration may lead to a pro-thrombotic state via acceleration in formation of fibrin clots. The present results may account, in part, for the association between nitrative stress and risk for coronary artery disease.

Received for publication, June 10, 2003 , and in revised form, December 12, 2003.

^* This work was supported by National Institutes of Health Grants P50-HL70128 (to J. W. W. and H. I.), HL70621, and HL62526 and GCRC Grant M01 RR018390 (to S. L. H.). 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.

^¶ Present address: Dept. of Biochemistry and Microbiology, Institute for Chemical Technology, Prague 16628, Czech Republic.

^¶¶ To whom correspondence should be addressed: Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Research Center, 34th St. and Civic Center Blvd., Philadelphia, PA 19104-4318. Tel.: 215-590-5320; Fax: 215-590-4267; E-mail: ischirop{at}mail.med.upenn.edu.

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