Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia
Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia
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DOI：
10.1523/jneurosci.21-19-07724.2001
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发表时间：
2001-10-01
影响因子：
5.3
通讯作者：
Lo, EH
中科院分区：
文献类型：
--
作者：
Asahi, M;Wang, XY;Lo, EH
细胞外蛋白水解的有害过程可能有助于急性脑损伤后组织损伤的进展。我们最近发现基质金属蛋白酶-9 （MMP-9）敲除小鼠对缺血性和创伤性脑有保护作用！受伤。在这项研究中，我们研究了其中的机制！聚焦。在血脑屏障、基质和白质中相关的MMP-9底物。MMP-9敲除小鼠和野生型小鼠进行短暂局灶性缺血。野生型脑缺血后MMP-9水平升高，主要表达于血管内皮。Western blot结果显示，缺血后血脑屏障相关蛋白和MMP-9底物闭塞带-1降解，但在敲除小鼠中减少。另一种血脑屏障相关蛋白闭塞蛋白没有检测到变化。相应地，通过Evans Blue评估的血脑屏障破坏，与野生型相比，MMP-9敲除小鼠的渗漏明显减弱。在白质中，与野生型相比，敲除小鼠的MMP-9底物髓鞘碱性蛋白的缺血降解显著减少，而其他非MMP底物髓鞘蛋白（蛋白脂质蛋白和DM20）没有降解。普遍存在的结构蛋白肌动蛋白或细胞外基质蛋白层粘连蛋白没有可检测到的变化。最后，与野生型相比，敲除小鼠的24小时病变体积显著减少。这些数据表明，短暂局灶性缺血后MMP-9基因敲除的保护作用可能是通过减少关键血脑屏障和白质成分的蛋白水解降解来介导的。
Deleterious processes of extracellular proteolysis may contribute to the progression of tissue damage after acute brain injury. We recently showed that matrix metalloproteinase-9 (MMP-9) knock-out mice were protected against ischemic, and traumatic brain! injury. In this study, we examined the mechanisms involved! by focusing. on relevant MMP-9 substrates in blood-brain barrier, matrix, and white matter. MMP-9 knock-out and wild-type mice were subjected to transient focal ischemia. MMP-9 levels increased after ischemia in wild-type brain, with expression primarily present in vascular endothelium. Western blots showed that the blood-brain: barrier-associated protein and MMP-9 substrate zonae occludens-1 was degraded after ischemia, but this was reduced in knock-out mice. There were no detectable changes in another blood-brain barrier-associated protein, occludin. Correspondingly, blood-brain barrier disruption assessed via Evans Blue, leakage was significantly attenuated in MMP-9 knock-out mice compared with wild types. In white matter, ischemic degradation: of the MMP-9 substrate myelin basic protein was significantly reduced in knock-out mice compared with wild types, whereas there was no degradation of other myelin proteins that are not MMP substrates (proteolipid protein and DM20). There were no detectable changes in the ubiquitous structural protein actin or the extracellular matrix protein laminin. Finally, 24 hr lesion volumes were significantly reduced in knock-out mice compared with wild types. These data demonstrate that the protective effects of MMP-9 gene knock-out after transient focal ischemia may be mediated by reduced proteolytic degradation of critical blood-brain barrier and white matter components.