Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid-mitochondrial apoptotic signaling pathway
Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid-mitochondrial apoptotic signaling pathway
复制标题
抑制星形胶质细胞中半胱氨酸组织蛋白酶 B 和 L 的激活，通过阻断 tBid-线粒体凋亡信号通路，有助于针对脑缺血的神经保护作用
DOI：
10.1002/glia.22645
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发表时间：
2014-06-01
期刊：
影响因子：
6.2
通讯作者：
Zhang, Hui-Ling
中科院分区：
文献类型：
--
作者：
Xu, Min;Yang, Lei;Zhang, Hui-Ling
组织蛋白酶在缺血性星形胶质细胞损伤中的作用尚不清楚。在这里，我们测试的假设，组织蛋白酶B和L的激活有助于缺血性星形胶质细胞损伤通过TBID-线粒体凋亡信号通路。在pMCAO大鼠模型中，CA-074 Me或组织蛋白酶B或组织蛋白酶L的选择性抑制剂Clik 148减少了梗死体积，改善了神经功能缺损，并增加了MAP（2）和GFAP水平。在OGD诱导的星形胶质细胞损伤中，CA-074 Me或Clik 148减少LDH泄漏并增加GFAP水平。在缺血皮质或OGD诱导的星形胶质细胞损伤中，Clik 148或CA-074 Me逆转了pMCAO或OGD诱导的3 h或6 h活性组织蛋白酶L或组织蛋白酶B的增加，逆转了pMCAO或OGD晚期12-24 h tBid的增加、线粒体细胞色素c（Cyt-c）的减少以及细胞质Cyt-c和活性caspase-3的增加。CA-074 Me或Clik 148在Bid活化早期6 h也降低胞质和线粒体tBid，增加线粒体Cyt-c，降低胞质Cyt-c和活性caspase-3。CA-074 Me或Clik 148阻断缺血后12 h缺血星形胶质细胞中pMCAO诱导的组织蛋白酶B或L从溶酶体释放到细胞质中以及caspase-3的活化。同时抑制组织蛋白酶B和组织蛋白酶L对OGD诱导的星形胶质细胞凋亡的保护作用优于单独使用每种抑制剂。这些结果表明，半胱氨酸组织蛋白酶B和组织蛋白酶L的激活在缺血星形胶质细胞中的抑制有助于通过阻断tBid-线粒体凋亡信号通路的神经保护。GLIA 2014;62：855-880
The roles of cathepsins in the ischemic astrocytic injury remain unclear. Here, we test the hypothesis that activation of cathepsin B and L contributes to the ischemic astrocyte injury via the tBid-mitochondrial apoptotic signaling pathways. In the rat models of pMCAO, CA-074Me or Clik148, a selective inhibitor of cathepsin B or cathepsin L, reduced the infarct volume, improved the neurological deficits and increased the MAP(2) and GFAP levels. In OGD-induced astrocyte injury, CA-074Me or Clik148 decreased the LDH leakage and increased the GFAP levels. In the ischemic cortex or OGD-induced astrocytes injury, Clik148 or CA-074Me reversed pMCAO or OGD-induced increase in active cathepsin L or cathepsin B at 3 h or 6 h, increase in tBid, reduction in mitochondrial cytochrome-c (Cyt-c) and increase in cytoplastic Cyt-c and active caspase-3 at 12-24 h of the late stage of pMCAO or OGD. CA-074Me or Clik148 also reduced cytosolic and mitochondrial tBid, increased mitochondrial Cyt-c and decreased cytoplastic Cyt-c and active caspase-3 at 6 h of the early stage of Bid activation. CA-074Me or Clik148 blocked the pMCAO-induced release of cathepsin B or L from the lysosomes into the cytoplasm and activation of caspase-3 in ischemic astrocytes at 12 h after ischemia. Concurrent inhibition of cathepsin B and cathepsin L provided better protection on the OGD-induced astrocytic apoptosis than obtained with separate use of each inhibitor. These results suggest that inhibition of the cysteine cathepsin B and cathepsin L activation in ischemic astrocytes contributes to neuroprotection via blocking the tBid-mitochondrial apoptotic signaling pathway. GLIA 2014;62:855-880