Fibrinogen nitrotyrosination after ischemic stroke impairs thrombolysis and promotes neuronal death

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• dc.contributor.author Ill-Raga, Gerard, 1982-ca
• dc.contributor.author Palomer, Ernestca
• dc.contributor.author Ramos Fernández, Eva, 1984-ca
• dc.contributor.author Guix Ràfols, Francesc Xavierca
• dc.contributor.author Bosch Morató, Mònica, 1986-ca
• dc.contributor.author Guivernau Almazán, Biuse, 1988-ca
• dc.contributor.author Tajes Orduña, Martaca
• dc.contributor.author Valls Comamala, Victòria, 1987-ca
• dc.contributor.author Jiménez Conde, Jordica
• dc.contributor.author Ois Santiago, Angel Javierca
• dc.contributor.author Gil Gómez, Gabrielca
• dc.contributor.author Alameda Quitllet, Franciscoca
• dc.contributor.author Roquer, Jaumeca
• dc.contributor.author Valverde, M. A. (Miguel Ángel), 1963-ca
• dc.contributor.author Muñoz López, Francisco José, 1964-ca
• dc.date.accessioned 2016-06-10T14:09:36Z
• dc.date.available 2016-06-10T14:09:36Z
• dc.date.issued 2015
• dc.description.abstract Ischemic stroke is an acute vascular event that compromises neuronal viability, and identification of the pathophysiological mechanisms is critical for its correct management. Ischemia produces increased nitric oxide synthesis to recover blood flow but also induces a free radical burst. Nitric oxide and superoxide anion react to generate peroxynitrite that nitrates tyrosines. We found that fibrinogen nitrotyrosination was detected in plasma after the initiation of ischemic stroke in human patients. Electron microscopy and protein intrinsic fluorescence showed that in vitro nitrotyrosination of fibrinogen affected its structure. Thromboelastography showed that initially fibrinogen nitrotyrosination retarded clot formation but later made the clot more resistant to fibrinolysis. This result was independent of any effect on thrombin production. Immunofluorescence analysis of affected human brain areas also showed that both fibrinogen and nitrotyrosinated fibrinogen spread into the brain parenchyma after ischemic stroke. Therefore, we assayed the toxicity of fibrinogen and nitrotyrosinated fibrinogen in a human neuroblastoma cell line. For that purpose we measured the activity of caspase-3, a key enzyme in the apoptotic pathway, and cell survival. We found that nitrotyrosinated fibrinogen induced higher activation of caspase 3. Accordingly, cell survival assays showed a more neurotoxic effect of nitrotyrosinated fibrinogen at all concentrations tested. In summary, nitrotyrosinated fibrinogen would be of pathophysiological interest in ischemic stroke due to both its impact on hemostasis - it impairs thrombolysis, the main target in stroke treatments - and its neurotoxicity that would contribute to the death of the brain tissue surrounding the infarcted area.ca
• dc.description.sponsorship This work was supported by the Spanish Ministry of Science and Innovation (SAF2012-38140; SAF 2009-10365); Fondo de Investigación Sanitaria (FIS PI13/00408, FIS PI13/00864, CP04-00112, PS09/00664 and Red HERACLESRD12/0042/0014, RD12/0042/0016 and RD12/0042/0020); FEDER Funds; Generalitat de Catalunya (SGR09-1369); and Fundació la Marató de TV3 (100310). Dr. A.M. Galán belongs to the Miguel Servet stabilization program of the Spanish Government's ISCIII research institute and “Direcció d'Estratègia i Coordinació del Departament de Salut” of the Generalitat de Catalunya.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Ill-Raga G, Palomer E, Ramos-Fernández E, Guix FX, Bosch-Morató M, Guivernau B et al. Fibrinogen nitrotyrosination after ischemic stroke impairs thrombolysis and promotes neuronal death. Biochimica et biophysica acta. 2015; 1852(3): 421-428. DOI 10.1016/j.bbadis.2014.12.007ca
• dc.identifier.doi http://dx.doi.org/10.1016/j.bbadis.2014.12.007
• dc.identifier.issn 0022-3042
• dc.identifier.uri http://hdl.handle.net/10230/26903
• dc.language.iso engca
• dc.publisher Elsevierca
• dc.relation.ispartof Biochimica et biophysica acta. 2015; 1852(3): 421-428
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2012-38140
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.bbadis.2014.12.007ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.keyword Apoptosis
• dc.subject.keyword Fibrinogen
• dc.subject.keyword Ischemic stroke
• dc.subject.keyword Nitric oxide
• dc.subject.keyword Peroxynitrite
• dc.subject.other Malalties coronàriesca
• dc.subject.other Òxid nítricca
• dc.title Fibrinogen nitrotyrosination after ischemic stroke impairs thrombolysis and promotes neuronal deathca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca