ETB RECEPTOR-MEDIATED MMP-9 ACTIVATION INDUCES VASOGENIC EDEMA VIA ZO-1 PROTEIN DEGRADATION FOLLOWING STATUS EPILEPTICUS
ETB RECEPTOR-MEDIATED MMP-9 ACTIVATION INDUCES VASOGENIC EDEMA VIA ZO-1 PROTEIN DEGRADATION FOLLOWING STATUS EPILEPTICUS
复制标题
DOI：
10.1016/j.neuroscience.2015.07.065
复制
发表时间：
2015-09-24
期刊：
影响因子：
3.3
通讯作者：
Kang, T. -C.
中科院分区：
文献类型：
--
作者：
Kim, J. Y.;Ko, A. -R.;Kang, T. -C.
血脑屏障（BBB）是由内皮细胞和血管周围的星形胶质细胞形成的，内皮细胞具有专门的紧密连接（TJ）。虽然脑损伤过程中BBB破坏导致血管源性水肿作为癫痫发生过程中的主要步骤之一，但关于血管源性水肿形成的分子和生理事件知之甚少。在本研究中，癫痫持续状态（SE）改变TJ蛋白（claudin-5，occludin和zonula occludens-1（ZO-1））在大鼠梨状皮质内皮细胞的表达和亚细胞定位。在TJ蛋白中，ZO-1表达的改变与内皮素B（ET B）受体介导的内皮型一氧化氮合酶（eNOS）激活有关，eNOS激活可增加基质金属蛋白酶9（MMP-9）活性。事实上，BQ 788（一种ETB受体拮抗剂）通过抑制内皮细胞中eNOS介导的MMP-9活化和ZO-1蛋白降解，有效地减弱了SE诱导的血管源性水肿，尽管星形胶质细胞终足与内皮细胞分离。因此，我们认为SE诱导的ETB受体/eNOS介导的MMP-9活化可能通过TJ蛋白降解导致内皮细胞功能受损，其参与了血管源性水肿的形成，而不依赖于血管周围星形胶质细胞的功能。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The blood-brain barrier (BBB) is formed by the endothelial cells with specialized tight junctions (TJs) lining the blood vessels and astroglial endfeet surrounding the blood vessels. Although BBB disruption during brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process, little is known about the molecular and physiological events concerning vasogenic edema formation. In the present study, status epilepticus (SE) changed the expressions and subcellular localizations of TJ proteins (claudin-5, occludin and zonula occludens-1 (ZO-1)) in endothelial cells of the rat piriform cortex. Among TJ proteins, the alteration in ZO-1 expression was relevant to endothelin B (ETB) receptor-mediated endothelial nitric oxide synthase (eNOS) activation, which increased matrix metalloproteinase-9 (MMP-9) activity. Indeed, BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced vasogenic edema by inhibiting eNOS-mediated MMP-9 activation and ZO-1 protein degradation in endothelial cells, although astroglial endfeet were detached from endothelial cells. Therefore, we suggest that SE-induced ETB receptor/eNOSmediated MMP-9 activation may lead to impairments of endothelial cell function via TJ protein degradation, which are involved in vasogenicedema formation independent of perivascular astroglial functions. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.