title: Pro-thrombotic state induced by post-translational modification of fibrinogen by reactive nitrogen species.
abstract: 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.
authors.affiliation: Stokes Research Institute and Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Caryn
authors.initials: C
authors.lastname: Vadseth
authors.forename: Jose M
authors.initials: JM
authors.lastname: Souza
authors.forename: Leonor
authors.initials: L
authors.lastname: Thomson
authors.forename: Amy
authors.initials: A
authors.lastname: Seagraves
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Nagaswami
authors.forename: Tomas
authors.initials: T
authors.lastname: Scheiner
authors.forename: Jim
authors.initials: J
authors.lastname: Torbet
authors.forename: Gaston
authors.initials: G
authors.lastname: Vilaire
authors.forename: Joel S
authors.initials: JS
authors.lastname: Bennett
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Murciano
authors.forename: Vladimir
authors.initials: V
authors.lastname: Muzykantov
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
mesh_terms: D001777:Blood Coagulation / Q000502:physiology; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism; D005337:Fibrin / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008855:Microscopy, Electron, Scanning; D011499:Protein Processing, Post-Translational / Q000502:physiology; D026361:Reactive Nitrogen Species / Q000737:chemistry / Q000378:metabolism*; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism
chemical_list: D026361:Reactive Nitrogen Species; D005337:Fibrin; D005340:Fibrinogen