title: Matrix metalloproteinase-10 effectively reduces infarct size in experimental stroke by enhancing fibrinolysis via a thrombin-activatable fibrinolysis inhibitor-mediated mechanism.
abstract: 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.
  
  
  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.
authors: Laboratory of Atherosclerosis, Division of Cardiovascular Science, CIMA, Avenida Pio XII, 55, 31008 Pamplona, Navarra, Spain. josuneor@unav.es
authors: J
authors: J
authors: Orbe
authors: J
authors: J
authors: Barrenetxe
authors: J A
authors: JA
authors: Rodriguez
authors: D
authors: D
authors: Vivien
authors: C
authors: C
authors: Orset
authors: W C
authors: WC
authors: Parks
authors: T P
authors: TP
authors: Birkland
authors: R
authors: R
authors: Serrano
authors: A
authors: A
authors: Purroy
authors: S
authors: S
authors: Martinez de Lizarrondo
authors: E
authors: E
authors: Angles-Cano
authors: J A
authors: JA
authors: Páramo
mesh_terms: D000818:Animals; D001760:Bleeding Time; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D020767:Intracranial Thrombosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D013917:Thrombin / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D005343:Fibrinolytic Agents; D013917:Thrombin; D010959:Tissue Plasminogen Activator; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10