17β-Estradiol Ameliorates Tight Junction Disruption via Repression of MMP Transcription
17β-Estradiol Ameliorates Tight Junction Disruption via Repression of MMP Transcription
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DOI：
10.1210/me.2015-1124
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发表时间：
2015-09-01
影响因子：
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通讯作者：
Ju, Bong-Gun
中科院分区：
文献类型：
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作者：
Na, Wonho;Lee, Jee Youn;Ju, Bong-Gun
毛细血管内皮细胞形成的血脑屏障(BBB)或血脊髓屏障(BSCB)为中枢神经系统(CNS)和循环血液之间提供了一道具有高度选择性通透性的物理屏障。已有研究表明，通过激活基质金属蛋白酶(MMPs)来破坏BBB/BSCB可导致中枢神经系统损伤后的进一步神经损伤。最近，在体外和体内模型中发现雌激素可以减弱BBB/BSCB的破坏。然而，雌激素介导的BBB/BSCB破坏减弱的分子机制尚未完全阐明。在本研究中，我们发现17β-雌二醇(E-2)抑制缺氧和糖剥夺/再灌注损伤的微血管内皮细胞bEnd.3中依赖于核因子-kappa B的MMP1b、MMP2、MMP3、MMP9、MMP10和MMP13基因的激活。E_2诱导ERα和核受体辅阻遏子在MMPs基因启动子上的核因子-kappaB结合部位募集。ER拮抗剂ICI182.780表现出与E-2相反的作用。我们进一步发现，2通过减少bEnd.3细胞在缺氧和葡萄糖剥夺-再灌注损伤中紧密连接蛋白的降解来减轻紧密连接的破坏。此外，E-2抑制了基质金属蛋白酶的表达上调，从而减少了损伤脊髓中BSCB的破坏。综上所述，我们通过体外和体内模型发现了雌激素BBB/BSCB干扰保护作用的分子机制。我们的研究表明，雌激素可能为维持中枢神经系统损伤后BBB/BSCB的完整性提供潜在的治疗干预。
The blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB) formed by capillary endothelial cells provides a physical wall between the central nervous system (CNS) and circulating blood with highly selective permeability. BBB/BSCB disruption by activation of matrix metalloproteinases (MMPs) has been shown to result in further neurological damage after CNS injury. Recently it has been discovered that estrogen attenuates BBB/BSCB disruption in in vitro and in vivo models. However, the molecular mechanism underlying the estrogen-mediated attenuation of BBB/BSCB disruption has not been elucidated fully. In the present study, we found that 17 beta-estradiol (E-2) suppresses nuclear factor-kappa B-dependent MMP-1b, MMP-2, MMP-3, MMP-9, MMP-10, and MMP-13 gene activation in microvessel endothelial bEnd.3 cells subjected to oxygen and glucose deprivation/reperfusion injury. E2 induced the recruitment of ER alpha and nuclear receptor corepressor to the nuclear factor-kappa B binding site on the MMPs' gene promoters. Consistently, ER antagonist ICI 182.780 showed opposite effects of E-2. We further found that 2 attenuates tight junction disruption through the decreased degradation of tight junction proteins in bEnd.3 cells subjected to oxygen and glucose deprivation-reperfusion injury. In addition, E-2 suppressed the up-regulation of MMP expression, leading to a decreased BSCB disruption in the injured spinal cord. In conclusion, we discovered the molecular mechanism underlying the protective role of estrogenin BBB/BSCB disruption using an in vitro and in vivo model. Our study suggests that estrogens may provide a potential therapeutic intervention for preserving BBB/BSCB integrity after CNS injury.