HMGB-1 promotes fibrinolysis and reduces neurotoxicity mediated by tissue plasminogen activator.

Abstract : Owing to its ability to generate the clot-dissolving protease plasmin, tissue plasminogen activator (tPA) is the only approved drug for the acute treatment of ischemic stroke. However, tPA also promotes hemorrhagic transformation and excitotoxic events. High mobility group box-1 protein (HMGB-1) is a non-histone transcription factor and a pro-inflammatory cytokine, which has also been shown to bind to both tPA and plasminogen. We thus investigated the cellular and molecular effects through which HMGB-1 could influence the vascular and parenchymal effects of tPA during ischemia. We demonstrate that HMGB-1 not only increases clot lysis by tPA, but also reduces the passage of vascular tPA across the blood-brain barrier, as well as tPA-driven leakage of the blood-brain barrier. In addition, HMGB-1 prevents the pro-neurotoxic effect of tPA, by blocking its interaction with N-methyl-D-aspartate (NMDA) receptors and the attendant potentiation of NMDA-induced neuronal Ca²⁺ influx. In conclusion, we show in vitro that HMGB-1 can promote the beneficial effects of tPA while counteracting its deleterious properties. We suggest that derivatives of HMGB-1, devoid of pro-inflammatory properties, could be used as adjunctive therapies to improve the overall benefit of tPA-mediated thrombolysis following stroke.
Type de document :
Article dans une revue
Journal of Cell Science, Company of Biologists, 2011, 124 (Pt 12), pp.2070-6. 〈10.1242/jcs.084392〉
Liste complète des métadonnées

Littérature citée [41 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-01296803
Contributeur : Benoit Roussel <>
Soumis le : vendredi 1 avril 2016 - 15:43:03
Dernière modification le : mardi 5 juin 2018 - 10:14:26
Document(s) archivé(s) le : lundi 14 novembre 2016 - 12:31:56

Fichier

Roussel J Cell Sci 2011.pdf
Fichiers produits par l'(les) auteur(s)

Identifiants

Collections

Citation

Benoit Roussel, Caroline Mysiorek, Ari Rouhiainen, Amandine Jullienne, Jerome Parcq, et al.. HMGB-1 promotes fibrinolysis and reduces neurotoxicity mediated by tissue plasminogen activator.. Journal of Cell Science, Company of Biologists, 2011, 124 (Pt 12), pp.2070-6. 〈10.1242/jcs.084392〉. 〈inserm-01296803〉

Partager

Métriques

Consultations de la notice

120

Téléchargements de fichiers

85