Suzuki Y, Nagai N, Umemura K, Collen D, Lijnen H R
Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
J Thromb Haemost. 2007 Aug;5(8):1732-9. doi: 10.1111/j.1538-7836.2007.02628.x. Epub 2007 May 21.
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.
To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke.
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.
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.
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.
组织型纤溶酶原激活剂（t-PA）已被批准用于治疗缺血性中风患者，但它可能会增加颅内出血（ICB）的风险。基质金属蛋白酶（MMPs）可通过纤溶酶原/纤溶系统激活，可能在缺血性中风后导致ICB。
探讨纤溶酶原、MMP-3和MMP-9在缺血性中风后与t-PA治疗相关的ICB中的作用。
使用血栓性大脑中动脉闭塞（MCA-O）模型，在纤溶酶原基因缺陷（Plg(-/-)）、基质溶解素-1（MMP-3(-/-)）或明胶酶B（MMP-9(-/-)）的小鼠及其相应的野生型（WT）同窝小鼠中研究ICB。还在C57BL/6 WT小鼠中研究了MMP-3和MMP-9的诱导情况。
t-PA（10 mg kg(-1)）诱导的ICB在Plg(-/-)（P < 0.05）和MMP-3(-/-)（P < 0.05）小鼠中明显少于WT小鼠，但在MMP-9(-/-)小鼠中并非如此。此外，t-PA治疗后给予广谱MMP抑制剂GM6001可显著降低MMP-3(+/+)小鼠的ICB（P < 0.05），但对MMP-3(-/-)小鼠无影响。MMP-3在缺血半球的表达明显增强；安慰剂治疗时，它仅在神经元中表达，而t-PA治疗时在内皮细胞中上调。虽然MMP-9在缺血脑的表达也明显增强，但在有或没有t-PA治疗的小鼠中，其数量和分布相当。
我们对基因缺陷小鼠的数据表明，对于t-PA治疗缺血性中风引起的ICB增加，纤溶酶原和MMP-3比MMP-9相对更重要。
