Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia
Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia
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DOI：
10.1038/jcbfm.2008.59
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发表时间：
2008-10-01
影响因子：
6.3
通讯作者：
Nozaki, Kazuhiko
中科院分区：
文献类型：
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作者：
Fujimoto, Motoaki;Takagi, Yasushi;Nozaki, Kazuhiko
增强的基质金属蛋白酶（MMPs）可引起脑缺血后血管源性水肿和出血性转化，影响缺血性损伤的程度。我们推测，内源性MMP抑制剂，组织抑制剂MMPs（TIMPs），是必不可少的，以防止缺血后血脑屏障（BBB）的破坏，通过调节MMPs的活性。本研究利用TIMP-1-/-和TIMP-2（-/）-小鼠证实了大脑中动脉闭塞30分钟后MMP-2和MMP-9以及TIMP家族的转变，并阐明了TIMP-1和TIMP-2在局灶性缺血中的作用。TIMP-1 mRNA表达逐渐增加，至再灌注后24 h。在TIMP-1（-/）-小鼠中，脑缺血后MMP-9蛋白表达和明胶分解活性显著高于WT小鼠，并伴有BBB破坏、神经元凋亡和缺血性损伤的加重。与此相反，TIMP-2基因缺失小鼠MMP表达和缺血性损伤程度无显着差异，尽管增加了伊文思蓝渗漏。提示TIMP-1可抑制MMP-9的活性，在脑缺血中发挥神经保护作用。
Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1-/- and TIMP-2(-/)-mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1(-/)-mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.