Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation
Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation
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DOI：
10.1097/01.wcb.0000122747.72175.47
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发表时间：
2004-07-01
影响因子：
6.3
通讯作者：
Lo, EH
中科院分区：
文献类型：
--
作者：
Lee, SR;Lo, EH
基质金属蛋白酶（MMPs）可能通过降解神经血管单元中的基质成分而参与脑缺血的病理生理。在这项研究中，作者记录了MMPs干扰细胞-基质相互作用并触发脑内皮细胞caspase介导的细胞毒性的途径。缺氧再氧化诱导内皮细胞毒性。zDEVD-fmk的细胞保护证实细胞死亡部分是由caspase介导的。caspase-3激活的时间分布与MMP-2和MMP-9的升高相匹配。MMP抑制剂显著降低caspase-3激活和内皮细胞死亡。基质纤维连接蛋白的降解证实了细胞外蛋白水解的存在。通过整合素激活抗体（8A2）增加整合素连接激酶信号传导可改善内皮细胞毒性。结果表明，MMP-9和MMP-2通过破坏细胞-基质相互作用和稳态整合素信号传导，参与caspase介导的缺氧-再氧化后脑内皮细胞死亡。
Matrix metalloproteinases (MMPs) may contribute to the pathophysiology of cerebral ischemia by degrading matrix components in the neurovascular unit. In this study, the authors document a pathway by which MMPs interfere with cell-matrix interactions and trigger caspase-mediated cytotoxicity in brain endothelial cells. Hypoxia-reoxygenation induced endothelial cytotoxicity. Cytoprotection with zDEVD-fmk confirmed that cell death was partly caspase mediated. The temporal profile of caspase-3 activation was matched by elevations in MMP-2 and MMP-9. MMP inhibitors significantly decreased caspase-3 activation and reduced endothelial cell death. Degradation of matrix fibronectin confirmed the presence of extracellular proteolysis. Increasing integrin-linked kinase signaling with the beta1 integrin-activating antibody (8A2) ameliorated endothelial cytotoxicity. The results suggest that MMP-9 and MMP-2 contribute to caspase-mediated brain endothelial cell death after hypoxia-reoxygenation by disrupting cell-matrix interactions and homeostatic integrin signaling.