BACKGROUND: Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke. OBJECTIVES: To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke. METHODS: Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg(-/-)), stromelysin-1 (MMP-3(-/-)), or gelatinase B (MMP-9(-/-)) and their corresponding wild-type (WT) littermates. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice. RESULTS: ICB induced by t-PA (10 mg kg(-1)) was significantly less than WT in Plg(-/-) (P < 0.05) and MMP-3(-/-) (P < 0.05) but not in MMP-9(-/-) mice. Furthermore, administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly (P < 0.05) in MMP-3(+/+) mice, but had no effect on MMP-3(-/-) mice. MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was up-regulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment. CONCLUSIONS: Our data with gene-deficient mice thus suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.
BACKGROUND:Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic strokepatients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke. OBJECTIVES: To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke. METHODS: Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg(-/-)), stromelysin-1 (MMP-3(-/-)), or gelatinase B (MMP-9(-/-)) and their corresponding wild-type (WT) littermates. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice. RESULTS: ICB induced by t-PA (10 mg kg(-1)) was significantly less than WT in Plg(-/-) (P < 0.05) and MMP-3(-/-) (P < 0.05) but not in MMP-9(-/-) mice. Furthermore, administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly (P < 0.05) in MMP-3(+/+) mice, but had no effect on MMP-3(-/-) mice. MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was up-regulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment. CONCLUSIONS: Our data with gene-deficient mice thus suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.
Authors: Irene de Miguel; Josune Orbe; Juan A Sánchez-Arias; José A Rodríguez; Agustina Salicio; Obdulia Rabal; Miriam Belzunce; Elena Sáez; Musheng Xu; Wei Wu; Haizhong Tan; Hongyu Ma; José A Páramo; Julen Oyarzabal Journal: ACS Med Chem Lett Date: 2018-04-16 Impact factor: 4.345
Authors: Robert C Kaplan; Nicholas L Smith; Stanley Zucker; Susan R Heckbert; Kenneth Rice; Bruce M Psaty Journal: Atherosclerosis Date: 2008-03-14 Impact factor: 5.162
Authors: Yoshihiro Murata; Anna Rosell; Robert H Scannevin; Kenneth J Rhodes; Xiaoying Wang; Eng H Lo Journal: Stroke Date: 2008-10-16 Impact factor: 7.914