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Stromelysin‐1 (MMP‐3) is critical for intracranial bleeding after t‐PA treatment of stroke in mice
Author(s) -
SUZUKI Y.,
NAGAI N.,
UMEMURA K.,
COLLEN D.,
LIJNEN H. R.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02628.x
Subject(s) - matrix metalloproteinase , stroke (engine) , medicine , intracranial bleeding , anticoagulant , mechanical engineering , engineering
Summary. 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.