Benchoua Alexandra, Braudeau Jérôme, Reis Aurélia, Couriaud Cécile, Onténiente Brigitte
Institut National de la Santé et de la Recherche Médicale, Université Paris Val-de-Marne, Crétoil, France.
J Cereb Blood Flow Metab. 2004 Nov;24(11):1272-9. doi: 10.1097/01.WCB.0000140272.54583.FB.
Cathepsins and caspases are two families of proteases that play pivotal roles in ischemic cell death. This study investigated the existence of a cross-talk between cathepsin B and proinflammatory caspases in stroke-induced cell death, as recently suggested by in vitro data. Cortical ischemic damage was induced in mice by distal and permanent occlusion of the middle cerebral artery. Cytoplasmic activation of cathepsin B was observed from the early stages of infarction, and displayed an activation pattern parallel to the activation pattern of caspase-1 and -11. Immunohistochemistry revealed the colocalization of cathepsin B with each caspase in cells of the infarct core. The apical position of cathepsin B in both caspase-activation cascades was confirmed by pretreatment of the animals with the cathepsin B inhibitor CA-074, which also potently protected cortical structures from ischemic damage, indicating involvement of the proteases in the lesion process. The results show that cathepsin B release is an early event following occlusion of cerebral arteries, which eventually triggers the activation of proinflammatory caspases in the absence of reperfusion. This new pathway may play a critical role in brain infarction by promoting inflammatory responses, and/or by amplifying the apoptotic process.
组织蛋白酶和半胱天冬酶是两类在缺血性细胞死亡中起关键作用的蛋白酶。本研究如近期体外实验数据所提示的那样，调查了组织蛋白酶B与促炎性半胱天冬酶在中风诱导的细胞死亡中是否存在相互作用。通过大脑中动脉远端永久性闭塞诱导小鼠皮质缺血损伤。在梗死早期观察到组织蛋白酶B的细胞质激活，其激活模式与半胱天冬酶-1和-11的激活模式平行。免疫组织化学显示在梗死核心细胞中组织蛋白酶B与每种半胱天冬酶共定位。用组织蛋白酶B抑制剂CA-074对动物进行预处理证实了组织蛋白酶B在两个半胱天冬酶激活级联反应中的顶端位置，这也有力地保护了皮质结构免受缺血损伤，表明这些蛋白酶参与了损伤过程。结果表明，组织蛋白酶B的释放是脑动脉闭塞后的早期事件，在无再灌注的情况下最终触发促炎性半胱天冬酶的激活。这一新途径可能通过促进炎症反应和/或放大凋亡过程在脑梗死中起关键作用。
