MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats
MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats
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MicroRNA-150 在大鼠大脑中动脉永久性闭塞后通过 Tie-2 调节血脑屏障通透性
DOI：
10.1096/fj.201500126
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发表时间：
2016-06-01
期刊：
影响因子：
4.8
通讯作者：
Hu, Bo
中科院分区：
文献类型：
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作者：
Fang, Zhi;He, Quan-Wei;Hu, Bo
血脑屏障（BBB）破坏的机制，涉及脑卒中后水肿和出血性转化，是重要的，但难以捉摸的。我们研究了microRNA-150（miR-150）介导的大鼠脑卒中后血脑屏障破坏机制。我们发现miR-150的上调增加了BBB的通透性，如在体内永久性大脑中动脉闭塞后通过MRI检测到的，以及在体外氧-葡萄糖剥夺后增加了脑微血管内皮细胞的通透性。上调miR-150后，缺血边界区关键紧密连接蛋白claudin-5的表达降低。我们在脑微血管内皮细胞中发现，过表达miR-150不仅降低了细胞存活率，而且降低了氧糖剥夺后claudin-5的表达水平。通过双荧光素酶实验，我们证实了miR-150可以直接调控血管生成素受体Tie-2。此外，用慢病毒递送的小干扰RNA沉默Tie-2逆转了miR-150对内皮通透性、细胞存活和claudin-5表达的影响。此外，脑卒中后使用特异性miR-150拮抗剂Escheromir-150治疗有助于BBB保护、梗死体积减少和神经功能缺损改善。总的来说，我们的研究结果表明，miR-150可以通过靶向Tie-2调节claudin-5表达和内皮细胞存活，从而影响大鼠永久性大脑中动脉闭塞后BBB的通透性，并且miR-150可能是治疗中风的潜在替代靶标。他，Q.- W.，李，Q.，陈锡铭L.，Baral，S.，金，H.- J.，朱玉是的，李，M.，夏，Y.- P.，毛湖，加-地Hu，B. MicroRNA-150通过Tie-2调节大鼠永久性大脑中动脉闭塞后血脑屏障通透性
The mechanism of blood-brain barrier (BBB) disruption, involved in poststroke edema and hemorrhagic transformation, is important but elusive. We investigated microRNA-150 (miR-150)-mediated mechanism in the disruption of BBB after stroke in rats. We found that up-regulation of miR-150 increased permeability of BBB as detected by MRI after permanent middle cerebral artery occlusion in vivo as well as increased permeability of brain microvascular endothelial cells after oxygen-glucose deprivation in vitro. The expression of claudin-5, a key tight junction protein, was decreased in the ischemic boundary zone after up-regulation of miR-150. We found in brain microvascular endothelial cells that overexpression of miR-150 decreased not only cell survival rate but also the expression levels of claudin-5 after oxygen-glucose deprivation. With dual-luciferase assay, we confirmed that miR-150 could directly regulate the angiopoietin receptor Tie-2. Moreover, silencing Tie-2 with lentivirus-delivered small interfering RNA reversed the effect of miR-150 on endothelial permeability, cell survival, and claudin-5 expression. Furthermore, poststroke treatment with antagomir-150, a specific miR-150 antagonist, contributed to BBB protection, infarct volume reduction, and amelioration of neurologic deficits. Collectively, our findings suggested that miR-150 could regulate claudin-5 expression and endothelial cell survival by targeting Tie-2, thus affecting the permeability of BBB after permanent middle cerebral artery occlusion in rats, and that miR-150 might be a potential alternative target for the treatment of stroke.Fang, Z., He, Q.-W., Li, Q., Chen, X.-L., Baral, S., Jin, H.-J., Zhu, Y.-Y., Li, M., Xia, Y.-P., Mao, L., Hu, B. MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats.