微小 RNA-132 通过保护 MCAO 小鼠血脑屏障减轻脑损伤。
MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice.
机构信息
Department of Neurosurgery, Affiliated Haikou Hospital, Xiangya Medical College of Central South University, Haikou, China; Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
Exp Neurol. 2019 Jun;316:12-19. doi: 10.1016/j.expneurol.2019.03.017. Epub 2019 Mar 28.
MicroRNAs (miRNAs) have been widely reported to induce posttranscriptional gene silencing and led to an explosion of new strategies for the treatment of human disease. It has been reported that the expression of MicroRNA-132 (miR-132) are altered both in the blood and brain after stroke. However, the effect of miR-132 on blood-brain barrier (BBB) disruption in ischemia stroke has not been studied. Here we will investigate the effects of miR-132 on the permeability of BBB after ischemic stroke and explore the potential mechanism underlying observed protection. Eight week-old mice were injected intracerebroventricularly with miR-132, antagomir-132 or agomir negative control (agomir-NC) 2 h before middle cerebral artery occlusion (MCAO), followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. BBB permeability and integrity were measured by Evan's blue extravasation and brain water content. The expression of tight junction proteins was detected by immnostaining and Western blots. The level of MiR-132 and its targeted gene Mmp9 were assayed. Treatment with exogenous MiR-132 (agomir-132) decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control mice. Agomir-132 increased the level of MiR-132 in brain tissue, suppressed the expression of MMP-9 mRNA and decreased the degradation of tight junction proteins VE-cadherin and β-Catenin in ischemic stroke mice. Inhibition of MMP-9 has a similar protective effect to agomir-132 on infraction volume, brain edema, and tight-junction protein expression after MCAO. Our results indicated that miR-132/MMP-9 axis might be a novel therapeutic target for BBB protection in ischemic stroke.
微小 RNA（miRNA）已被广泛报道能诱导转录后基因沉默，并为人类疾病的治疗带来了新策略的爆发。据报道，中风后血液和大脑中的 MicroRNA-132（miR-132）表达都发生了改变。然而，miR-132 对缺血性中风中血脑屏障（BBB）破坏的影响尚未研究。在这里，我们将研究 miR-132 对缺血性中风后 BBB 通透性的影响，并探讨观察到的保护作用的潜在机制。8 周大的小鼠在大脑中动脉闭塞（MCAO）前 2 小时通过脑室内注射 miR-132、antagomir-132 或 agomir 阴性对照（agomir-NC），然后在 MCAO 后 24 小时进行动物行为测试和梗死体积测量。通过 Evans 蓝渗出和脑水含量测量 BBB 通透性和完整性。通过免疫染色和 Western blot 检测紧密连接蛋白的表达。检测 MiR-132 及其靶基因 Mmp9 的水平。与对照组小鼠相比，外源性 MiR-132（agomir-132）治疗可降低梗死体积、减轻脑水肿、改善神经功能。Agomir-132 增加脑组织中 MiR-132 的水平，抑制 MMP-9 mRNA 的表达，并减少缺血性中风小鼠中紧密连接蛋白 VE-cadherin 和 β-Catenin 的降解。抑制 MMP-9 对 MCAO 后梗死体积、脑水肿和紧密连接蛋白表达的保护作用与 agomir-132 相似。我们的研究结果表明，miR-132/MMP-9 轴可能是缺血性中风中 BBB 保护的一个新的治疗靶点。
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