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首页> 外文期刊>The European Journal of Neuroscience >Attenuation of urokinase activity during experimental ischaemia protects the cerebral barrier from damage through regulation of matrix metalloproteinase-2 and NAD(P)H oxidase
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Attenuation of urokinase activity during experimental ischaemia protects the cerebral barrier from damage through regulation of matrix metalloproteinase-2 and NAD(P)H oxidase

机译：实验性缺血期间尿激酶活性的减弱可通过调节基质金属蛋白酶2和NAD（P）H氧化酶来保护脑屏障免受损害

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摘要

Ischaemic injury impairs the integrity of the blood-brain barrier (BBB). In this study, we investigated the molecular causes of this defect with regard to the putative correlations among NAD(P)H oxidase, plasminogen-plasmin system components, and matrix metalloproteinases. Hence, the activities of NAD(P)H oxidase, matrix metalloproteinase-2, urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA), and superoxide anion levels, were assessed in human brain microvascular endothelial cells (HBMECs) exposed to oxygen-glucose deprivation (OGD) alone or OGD followed by reperfusion (OGD + R). The integrity of an in vitro model of BBB comprising HBMECs and astrocytes was studied by measuring transendothelial electrical resistance and the paracellular flux of albumin. OGD with or without reperfusion (OGD ± R) radically perturbed barrier function while concurrently enhancing uPA, tPA and NAD(P)H oxidase activities and superoxide anion release in HBMECs. Pharmacological inactivation of NAD(P)H oxidase attenuated OGD ± R-mediated BBB damage through modulation of matrix metalloproteinase-2 and tPA, but not uPA activity. Overactivation of NAD(P)H oxidase in HBMECs via cDNA electroporation of its p22-phox subunit confirmed the involvement of tPA in oxidase-mediated BBB disruption. Interestingly, blockade of uPA or uPA receptor preserved normal BBB function by neutralizing both NAD(P)H oxidase and matrix metalloproteinase-2 activities. Hence, selective targeting of uPA after ischaemic strokes may protect cerebral barrier integrity and function by concomitantly attenuating basement membrane degradation and oxidative stress.
机译：缺血性损伤会损害血脑屏障（BBB）的完整性。在这项研究中，我们调查了与NAD（P）H氧化酶，纤溶酶原-纤溶酶系统组成部分和基质金属蛋白酶之间的假定相关性相关的缺陷的分子原因。因此，在人脑微血管内皮细胞中评估了NAD（P）H氧化酶，基质金属蛋白酶-2，尿激酶型纤溶酶原激活物（uPA）和组织型纤溶酶原激活物（tPA）的活性以及超氧化物阴离子水平（ HBMEC）单独暴露于氧-葡萄糖剥夺（OGD）或暴露于OGD，然后再灌注（OGD + R）。通过测量跨内皮电阻和白蛋白的细胞旁通量，研究了包含HBMEC和星形胶质细胞的BBB体外模型的完整性。具有或不具有再灌注（OGD±R）的OGD会扰动屏障功能，同时增强HBMECs中的uPA，tPA和NAD（P）H氧化酶活性和超氧阴离子释放。 NAD（P）H氧化酶的药理失活通过调节基质金属蛋白酶2和tPA而不是uPA活性来减弱OGD±R介导的BBB损伤。通过其p22-phox亚基的cDNA电穿孔，HBMECs中NAD（P）H氧化酶的过度活化证实了tPA参与了氧化酶介导的BBB破坏。有趣的是，通过中和NAD（P）H氧化酶和基质金属蛋白酶2的活性，uPA或uPA受体的阻滞保留了正常的BBB功能。因此，缺血性中风后uPA的选择性靶向可通过同时减弱基底膜的降解和氧化应激来保护脑屏障的完整性和功能。

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