title: Fibrinogen beta-chain tyrosine nitration is a prothrombotic risk factor.
abstract: Elevated levels of circulating fibrinogen are associated with an increased risk of atherothrombotic diseases although a causative correlation between high levels of fibrinogen and cardiovascular complications has not been established. We hypothesized that a potential mechanism for an increased prothrombotic state is the post-translational modification of fibrinogen by tyrosine nitration. Mass spectrometry identified tyrosine residues 292 and 422 at the carboxyl terminus of the beta-chain as the principal sites of fibrinogen nitration in vivo. Immunoelectron microscopy confirmed the incorporation of nitrated fibrinogen molecules in fibrin fibers. The nitration of fibrinogen in vivo resulted in four distinct functional consequences: increased initial velocity of fibrin clot formation, altered fibrin clot architecture, increased fibrin clot stiffness, and reduced rate of clot lysis. The rate of fibrin clot formation and clot architecture was restored upon depletion of the tyrosine-nitrated fibrinogen molecules. An enhanced response to the knob "B" mimetic peptides Gly-His-Arg-Pro(am) and Ala-His-Arg-Pro(am) suggests that incorporation of nitrated fibrinogen molecules accelerates fibrin lateral aggregation. The data provide a novel biochemical risk factor that could explain epidemiological associations of oxidative stress and inflammation with thrombotic complications.
authors.affiliation: Stokes Research Institute and Departments of Pediatrics and Pharmacology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Parastatidis
authors.forename: Leonor
authors.initials: L
authors.lastname: Thomson
authors.forename: Anne
authors.initials: A
authors.lastname: Burke
authors.forename: Irina
authors.initials: I
authors.lastname: Chernysh
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Nagaswami
authors.forename: Jetze
authors.initials: J
authors.lastname: Visser
authors.forename: Sheryl
authors.initials: S
authors.lastname: Stamer
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Liebler
authors.forename: George
authors.initials: G
authors.lastname: Koliakos
authors.forename: Harry F G
authors.initials: HF
authors.lastname: Heijnen
authors.forename: Garret A
authors.initials: GA
authors.lastname: Fitzgerald
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
mesh_terms: D000293:Adolescent; D000328:Adult; D005337:Fibrin / Q000737:chemistry; D005340:Fibrinogen / Q000737:chemistry*; D006801:Humans; D016253:Microscopy, Immunoelectron / Q000379:methods; D008875:Middle Aged; D009584:Nitrogen / Q000737:chemistry; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012307:Risk Factors; D013927:Thrombosis / Q000175:diagnosis / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry*
chemical_list: C115499:BBeta fibrinogen; D014443:Tyrosine; D005337:Fibrin; D005340:Fibrinogen; D009584:Nitrogen