Matrix metalloproteinase-10 effectively reduces infarct size in experimental stroke by enhancing fibrinolysis via a thrombin-activatable fibrinolysis inhibitor-mediated mechanism

BACKGROUND: The fibrinolytic and matrix metalloproteinase (MMP) systems cooperate in thrombus dissolution and extracellular matrix proteolysis. The plasminogen/plasmin system activates MMPs, and some MMPs have been involved in the dissolution of fibrin by targeting fibrin(ogen) directly or by collaborating with plasmin. MMP-10 has been implicated in inflammatory/thrombotic processes and vascular integrity, but whether MMP-10 could have a profibrinolytic effect and represent a promising thrombolytic agent is unknown. METHODS AND RESULTS: The effect of MMP-10 on fibrinolysis was studied in vitro and in vivo, in MMP-10-null mice (Mmp10(-/-)), with the use of 2 different murine models of arterial thrombosis: laser-induced carotid injury and ischemic stroke. In vitro, we showed that MMP-10 was capable of enhancing tissue plasminogen activator-induced fibrinolysis via a thrombin-activatable fibrinolysis inhibitor inactivation-mediated mechanism. In vivo, delayed fibrinolysis observed after photochemical carotid injury in Mmp10(-/-) mice was reversed by active recombinant human MMP-10. In a thrombin-induced stroke model, the reperfusion and the infarct size in sham or tissue plasminogen activator-treated animals were severely impaired in Mmp10(-/-) mice. In this model, administration of active MMP-10 to wild-type animals significantly reduced blood reperfusion time and infarct size to the same extent as tissue plasminogen activator and was associated with shorter bleeding time and no intracranial hemorrhage. This effect was not observed in thrombin-activatable fibrinolysis inhibitor-deficient mice, suggesting thrombin-activatable fibrinolysis inhibitor inactivation as one of the mechanisms involved in the MMP-10 profibrinolytic effect. CONCLUSIONS: A novel profibrinolytic role for MMP-10 in experimental ischemic stroke is described, opening new pathways for innovative fibrinolytic strategies in arterial thrombosis

Brain plasminogen system

Endothelial cells, glial and neuronal cells, representing the principal sources of plasminogen activator (tPA and uPA), are in close interaction in the neurovascular unit. Formation of plasmin at the surface of endothelial cells and neurons has important consequences on these cells (apoptosis of endothelial cells and detachment/aggregation of neurons). The plasminogen activation system is also known to participate in various inflammatory conditions of the central nervous system. In such pathologies, beyond circulating plasminogen, the origin of plasminogen is still a matter of debate. First, we have investigated the presence of plasminogen in human cerebro-spinal fluids. The presence of plasminogen and the activity of plasmin, tPA and uPA in inflammatory diseases (GBS, Guillain Barre Syndrome patients, n = 14; MS, Multiple sclerosis, n = 9) and also in non-inflammatory diseases (n = 13) were studied. Western blotting, zymography and chromogenic detection were used to evaluate antigens and activity of plasmin(ogen), uPA and tPA. In human, plasminogen was detectable in both inflammatory (66%) and non-inflammatory (65%) patients. Plasminogen was found in larger concentration in inflammatory diseases (4.6 nM in GBS, 6.5 nM in MS and 2.2 nM in non inflammatory diseases). Active plasmin was detected in GBS and MS patients (3.55 nM vs. 2.6 nM). uPA was detectable in a minority of patients (15% of GBS, 20% if MS and 7% of non-inflammatory diseases), and tPA was not detect. To further investigate the origin of plasminogen in the central nervous system, we are currently exploring the presence of plasminogen in mouse parenchyma in physiological and inflammatory conditions by immuno-histochemistry. In conclusion, we have shown that a plasminogen activation system is detectable in CSF of patient with inflammatory and non-inflammatory diseases. The role of these proteolytic messengers in diseases outcome remains to be determined

Requirements for Ad Hoc IP Address Autoconfiuguration

Draft IETF, http://www-users.cs.umn.edu/~jjeong/publications/ietf-internet-draft/draft-jeong-manet-addr-autoconf-reqts-01.tx

Nicotinamide riboside, a form of vitamin B 3 , protects against excitotoxicity-induced axonal degeneration

International audienc

GpIb -VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

International audienceInteractions between platelet glycoprotein (Gp) IIb/IIIa and plasma proteins mediate platelet cross-linking in arterial thrombi. However, GpIIb/IIIa inhibitors fail to disperse platelet aggregates after myocardial infarction or ischemic stroke. These results suggest that stability of occlusive thrombi involves additional and as-yet-unidentified mechanisms. In the present study, we investigated the mechanisms driving platelet cross-linking during occlusive thrombus formation. Using computational fluid dynamic simulations and in vivo thrombosis models, we demonstrated that the inner structure of occlusive thrombi is heterogeneous and primarily determined by the rheological conditions that prevailed during thrombus growth. Unlike the first steps of thrombus formation, which are GpIIb/IIIa-dependent, our findings reveal that closure of the arterial lumen is mediated by GpIbα-von Willebrand Factor (VWF) interactions. Accordingly, disruption of platelet cross-linking using GpIbα-VWF inhibitors restored vessel patency and improved outcome in a mouse model of ischemic stroke, although the thrombi were resistant to fibrinolysis or traditional antithrombotic agents. Overall, our study demonstrates that disruption of GpIbα-VWF interactions restores vessel patency after occlusive thrombosis by specifically disaggregating the external layer of occlusive thrombi, which is constituted of platelet aggregates formed under very high shear rates