Activation of proinflammatory caspases by cathepsin B in focal cerebral ischemia
Activation of proinflammatory caspases by cathepsin B in focal cerebral ischemia
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DOI：
10.1097/01.wcb.0000140272.54583.fb
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发表时间：
2004-11-01
影响因子：
6.3
通讯作者：
Onténiente, B
中科院分区：
文献类型：
--
作者：
Benchoua, A;Braudeau, J;Onténiente, B
组织蛋白酶和半胱天冬酶是在缺血性细胞死亡中起关键作用的两个蛋白酶家族。本研究调查了组织蛋白酶B和促炎性半胱天冬酶在中风诱导的细胞死亡中的相互作用，正如最近的体外数据所表明的那样。通过大脑中动脉的远端和永久闭塞在小鼠中诱导皮质缺血性损伤。从梗死早期就观察到组织蛋白酶B的胞质激活，并显示与caspase-1和-11的激活模式平行的激活模式。免疫组织化学显示，组织蛋白酶B与梗死核心细胞中的每种半胱天冬酶共定位。组织蛋白酶B抑制剂CA-074预处理动物证实了组织蛋白酶B在两个半胱天冬酶激活级联反应中的顶端位置，CA-074也有效地保护皮质结构免受缺血性损伤，表明蛋白酶参与了损伤过程。结果表明，组织蛋白酶B释放是脑动脉闭塞后的早期事件，其最终在没有再灌注的情况下触发促炎性半胱天冬酶的激活。这种新的通路可能通过促进炎症反应和/或通过放大凋亡过程在脑梗死中发挥关键作用。
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.