MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5
MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5
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MicroRNA-130a 通过靶向 Homebox A5 调节脑缺血引起的血脑屏障通透性。FASEB J.
DOI：
10.1096/fj.201700139rrr
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发表时间：
2018-02-01
期刊：
影响因子：
4.8
通讯作者：
Hu, Bo
中科院分区：
文献类型：
--
作者：
Wang, Yong;Wang, Meng-Die;Hu, Bo
血脑屏障（BBB）的破坏在脑缺血引起的脑损伤中起着重要作用，在缺血期间保持BBB的完整性可以减轻脑损伤。我们使用大鼠大脑中动脉闭塞和细胞氧-葡萄糖剥夺模型来检测miR-130 a在缺血性BBB破坏中的作用。我们发现缺血显著增加microRNA-130 a（miR-130 a）水平，并且miR-130 a主要来自脑微血管内皮细胞。miR-130 a的拮抗剂Antagomir-130 a可减轻脑水肿，降低BBB通透性，减少梗死体积，改善神经功能。miR-130 a模拟物诱导的miR-130 a过表达增加了单层通透性，而miR-130 a抑制剂对miR-130 a的细胞间抑制抑制了氧-葡萄糖剥夺诱导的单层通透性增加。此外，双荧光素酶报告基因系统表明Homeobox A5是miR-130 a的直接靶点。MiR-130 a通过抑制同源框A5表达，可以下调闭合蛋白，从而增加BBB通透性。我们的研究结果表明，miR-130 a可能与缺血诱导的BBB功能障碍有关，并可作为治疗缺血性卒中的靶点。
Blood-brain barrier (BBB) disruption plays a critical role in brain injury induced by cerebral ischemia, and preserving BBB integrity during ischemia could alleviate cerebral injury. We examined the role of miR-130a in ischemic BBB disruption by using models of rat middle cerebral artery occlusion and cell oxygen-glucose deprivation. We found that ischemia significantly increased microRNA-130a (miR-130a) level and that miR-130a was predominantly from brain microvascular endothelial cells. Antagomir-130a, an antagonist of miR-130a, could attenuate brain edema, lower BBB permeability, reduce infarct volume, and improve neurologic function. MiR-130a overexpression induced by miR-130a mimic increased monolayer permeability, and intercellular inhibition of miR-130a by a miR-130a inhibitor suppressed oxygen-glucose deprivation-induced increase in monolayer permeability. Moreover, dual luciferase reporter system showed that Homeobox A5 was the direct target of miR-130a. MiR-130a, by inhibiting Homeobox A5 expression, could down-regulate occludin, thereby increasing BBB permeability. Our results suggested that miR-130a might be implicated in ischemia-induced BBB dysfunction and serve as a target for the treatment of ischemic stroke.