Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice.
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.


OBJECTIVE
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.
Suzuki
Y
Y
Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
Nagai
N
N
Umemura
K
K
Collen
D
D
Lijnen
H R
HR
D000818:Animals; D005786:Gene Expression Regulation; D020300:Intracranial Hemorrhages / Q000201:enzymology* / Q000209:etiology; D007511:Ischemia / Q000150:complications; D019278:Matrix Metalloproteinase 3 / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D010919:Placebos; D020521:Stroke / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D010919:Placebos; D010959:Tissue Plasminogen Activator; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse