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. 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. Epidemiological studies have indicated that increased levels of circulating fibrinogen is an independent predictor of coronary heart disease and in some cases of premature death from cardiovascular disease, although a causative relationship between high levels of fibrinogen and cardiovascular disease has not been firmly established (1Wilhelmsen L. Svardsudd K. Korsan-Bengtsen K. Larsson B. Welin L. Tibblin G. N. Engl. J. Med. 1984; 311: 501-505Crossref PubMed Scopus (1554) Google Scholar, 2Kannel W.B. Wolf P.A. Castelli W.P. D'Agostino R.B. J. Am. Med. Assoc. 1987; 258: 1183-1186Crossref PubMed Scopus (1435) Google Scholar, 3Thompson S.G. Kienast J. Pyke S.D.M. Haverkate F. van de Loo J.C.W. N. Engl. J. Med. 1995; 332: 635-641Crossref PubMed Scopus (1598) Google Scholar, 4Salomaa V. Stinson V. Kark J.D. Folsom A.R. Davis C.E. Wu K.K. Circulation. 1995; 91: 284-290Crossref PubMed Google Scholar). Fibrinogen is a multifunctional protein essential for hemostasis. It is a 340-kDa glycoprotein, consisting of three non-identical peptide chains Aα, Bβ, and γ, which are linked together by 29 disulfide bonds (5Weisel J.W. Stauffacher C.V. Bullit E. Cohen C. Science. 1985; 230: 1388-1391Crossref PubMed Scopus (223) Google Scholar). During coagulation, the soluble fibrinogen is converted to insoluble fibrin polymers. The process is initiated by thrombin, a serine protease, which catalyzes the cleavage first of two fibrinopeptides from the amino termini of the Aα chains and then two fibrinopeptides from the amino termini Bβ chains. Upon release of the fibrinopeptides, the remaining fibrin monomers aggregate spontaneously to form ordered fibrin polymers (5Weisel J.W. Stauffacher C.V. Bullit E. Cohen C. Science. 1985; 230: 1388-1391Crossref PubMed Scopus (223) Google Scholar). The clot is stabilized by the formation of covalent bonds introduced by the action of a transglutaminase, factor XIII (6Murthy S.N.P. Wilson J.H. Likas J.H. Velkich Y. Weisel J.W. Lonard L. Proc. Natl. Acad. Sci. U. S. A. 1999; 97: 44-48Crossref Scopus (29) Google Scholar). Under physiological conditions, fibrinolysis is dependent on the binding of circulating plasminogen and tissue-type plasminogen activator (tPA) 1The abbreviations used are: tPA, tissue-type plasminogen activator; HPLC, high pressure liquid chromatography; MPO, myeloperoxidase; HOCl, hypochlorous acid; ME, microemboli; ARDS, acute respiratory distress syndrome; ANOVA, analysis of variance. to fibrin clots. Urokinase and tPA convert plasminogen to the active protease plasmin, which then cleaves fibrin polymers to soluble fragments completing the coagulation and clot resolution cycle. A major cause of vascular injury leading to the development of atherosclerosis is oxidative stress (7White C.R. Brock T.A. Chang L.Y. Crapo J. Briscoe P. Ku D. Bradley W.A. Gianturco S.H. Gore J. Freeman B.A. Tarpey M.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1044-1048Crossref PubMed Scopus (660) Google Scholar, 8Berliner J.A. Heinecke J.W. Free Radic. Biol. 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In this study we identified and quantified nitrated fibrinogen in the plasma of patients with documented coronary artery disease. In a series of experiments the effects of nitration on the kinetics of fibrin formation, factor XIII cross-linking, fibrin architecture and rheology, platelet aggregation and binding, and lysis by plasmin were determined and contrasted with oxidized and control fibrinogen. Human Studies—Sequential patients presenting to the Cardiology Section of the Cleveland Clinic Foundation or responding to local advertisements were enrolled. To be classified as having coronary artery disease, patients had to have a documented of coronary artery coronary or a of or in or major coronary demonstrated by coronary To be a had to have no of coronary artery disease, no artery disease, or of of or heart patients and the of the Cleveland Clinic Foundation the study plasma with protein in lysis the protease for in to the The for and of J.M. C. S. B. H. Am. J. PubMed Google Scholar) to the and The were then for with protein and then for The were three for with lysis the protease The were by for and of and to the The were for and for and the then by The proteins were on and to The with and then with the with of Fibrinogen from Human A to fibrinogen from coronary artery disease and control fibrinogen to protein A and with the plasma in and to the protein were with of fibrinogen were with and in were to a a in the by or protein were and by as levels were determined by with and an as (17Shishehbor M.H. Aviles R.J. Brennan M.L. Fu X. Goormastic M. Pearce P.L. Gokce N. Keaney J.F. Penn M.S. Sprecher D.L. Vita J. Hazen S.L. J. Am. Med. Assoc. 2003; 289: 1675-1680Crossref PubMed Scopus (409) Google Scholar, M.L. Wu Fu X. H. C. L. E. H. Hazen S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). and of human fibrinogen which of factor and with in The fibrinogen then a of fibrinogen were two and an of to Fibrinogen exposed to in the or of for In the of and in physiological of catalyzes the formation of hypochlorous a and In the of in to HOCl, catalyzes the formation of nitrogen an and nitrating M.L. Wu Fu X. H. C. L. E. H. Hazen S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. L. M. P. A. White C.R. Brennan M.L. Freeman B.A. J. Investig. PubMed Scopus Google Scholar, J. J.A. A. Heinecke J.W. J. Investig. 2002; PubMed Scopus Google Scholar). a control fibrinogen exposed to Fibrinogen exposed to is in and with nitrogen and to release nitric and in the rate is which with a rate of to form The were for which is the of and to the levels in the a fibrinogen exposed to in the of to nitric for Under these conditions, fibrinogen is exposed to nitric with the the were to a and were with the the nitration of fibrinogen by with and by liquid analysis whereas by the formation of as E. J.A. Free Radic. Biol. Med. 1995; PubMed Scopus Google Scholar). that exposure to and not in the results in nitration of tyrosine in three fibrinogen chains. The nitration of fibrinogen not in in fibrinogen as determined by the of the control and nitrated fibrinogen not Under conditions, exposure of fibrinogen to or not in covalent protein of clot formation of control fibrinogen and exposed to nitrating and of of of in a initiated by the of of human to fibrinogen in formation as the increase in a formation in human plasma initiated by of and from The of in plasma to in with a The formation of fibrinopeptides A and of by and factor XIII fibrinogen and fibrin as J.W. C. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). clots made were for as J.W. C. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). were in and for clots three high resolution from were and which the of the a and on the and from the and of the clot as in Weisel J.W. Lonard L. Biophys. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). were in clots between in a for permeation studies Weisel J.W. Lonard L. Biophys. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). clot three and three clots were for on of lysis by of tPA as Y. White J. Weisel J.W. 1998; PubMed Google Scholar, D. C. J. C. G. Weisel J.W. Arterioscler. Thromb. Vasc. Biol. 20: PubMed Scopus Google Scholar). The lysis for of the The plasmin and the plasmin of fibrin clots were as Y. White J. Weisel J.W. 1998; PubMed Google Scholar). The for the and lysis of as in D. L. K. S. M.A. Am. J. 2002; Scholar, K. J. L. J. PubMed Google Scholar). and of on a in the of and of from to M.A. C. A. N. 1997; PubMed Scopus Google Scholar). platelet to control and nitrated fibrinogen were and by the J.S. G. J. Investig. PubMed Scopus Google Scholar) a of Nitrated Fibrinogen in with of coronary artery disease patients with a the proteins with a that a of fibrinogen nitrated in coronary artery disease plasma In to and the of nitrated fibrinogen in coronary artery disease and control fibrinogen in which the of a to protein A. The of the to nitrated fibrinogen by in nitrated fibrinogen The in the fibrinogen for the plasma The fibrinogen then in to the protein levels by with and an (17Shishehbor M.H. Aviles R.J. Brennan M.L. Fu X. Goormastic M. Pearce P.L. Gokce N. Keaney J.F. Penn M.S. Sprecher D.L. Vita J. Hazen S.L. J. Am. Med. Assoc. 2003; 289: 1675-1680Crossref PubMed Scopus (409) Google Scholar, M.L. Wu Fu X. H. C. L. E. H. Hazen S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The were to the levels of tyrosine to in fibrinogen levels A increase in the levels of nitrated fibrinogen in coronary artery disease patients as with of Fibrinogen on The of fibrin by by in in human plasma the of from coronary artery disease patients and is in The of fibrinogen from patients with coronary artery disease showed a a in the and increased as with fibrinogen from plasma of The in fibrinogen were not to fibrinogen in plasma the of tyrosine in the fibrinogen for these and for the coronary disease patients in and and and for the control the nitrotyrosine in these as of and for the coronary artery disease patients and and for the To the of fibrinogen nitration on and of the nitrated and oxidized were by in and The of nitration exposure to and or and tyrosine as by liquid (17Shishehbor M.H. Aviles R.J. Brennan M.L. Fu X. Goormastic M. Pearce P.L. Gokce N. Keaney J.F. Penn M.S. Sprecher D.L. Vita J. Hazen S.L. J. Am. Med. Assoc. 2003; 289: 1675-1680Crossref PubMed Scopus (409) Google Scholar, M.L. Wu Fu X. H. C. L. E. H. Hazen S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). were in to of the coronary disease that the of of in that the of fibrin by by in show a in the of fibrinogen with as with the protein oxidized by and The increase in with fibrinogen exposed to nitration in the of as with control or fibrinogen exposed to in the of In these experiments to the in coronary artery disease the in fibrin the rate of for the first the increased and the in the control suggesting of clot the rate of for the first the for the increased as a of the of fibrinogen nitration The increase in the rate of of fibrinogen exposed to nitration in the of oxidized fibrinogen. Fibrinogen that exposed first to and oxidized by of or fibrinogen that exposed first to and then to showed the increase in rate of as fibrinogen exposed to In fibrinogen exposed to or nitric or to show in the rate of The increase in the rate of not to acceleration in of A and by the between control and nitrated fibrinogen XIII factor XIII fibrinogen and Fibrinogen by factor XIII is not between control and nitrated fibrinogen factor XIII of fibrin in the nitrated fibrinogen in control as by the of the Aα and chains of fibrinogen of on and architecture of the fibrin clots formed by and oxidized by as J.W. C. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). clots formed by exposed to nitrating are from control or oxidized The clots made from exposed to or are made of the that the fibers be the fibrin clot made by nitrated is composed of large bundles of the thin fibrin which for the the of twisted fibers in nitrated A of large are in fibrin clots made of nitrated in to the and fibrin of the oxidized fibrinogen in the architecture of the fibrin clots be to have consequences on the of the in the permeation or were determined by made a pressure and for of the clot Weisel J.W. Lonard L. Biophys. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The permeation of clots made from exposed to or significantly the control increase in permeation is for by the of large as by A decrease in the in the fibrin clots made of oxidized the in these clots decreased as with and of the analysis of analysis of analysis of analysis of analysis of analysis of analysis of analysis of analysis of analysis of analysis of in a then by of the of the fibrin clots made from nitrated or oxidized fibrinogen. exposed to nitrating and oxidized produced clots that were control by the decrease in storage modulus G′ that is to the of the clot were no in the modulus or the of to for clots made from exposed to nitrating and and of fibrinogen with plasmin in the of results in the of fibrinogen to and fibrinogen fragments Y. White J. Weisel J.W. 1998; PubMed Google Scholar, D. C. J. C. G. Weisel J.W. Arterioscler. Thromb. Vasc. 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