MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice
MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice
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MicroRNA-132 通过保护 MCAO 小鼠的血脑屏障减轻脑损伤
DOI：
10.1016/j.expneurol.2019.03.017
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发表时间：
2019-06-01
影响因子：
5.3
通讯作者：
Hu, Qin
中科院分区：
文献类型：
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作者：
Zuo, Xiaokun;Lu, Jianfei;Hu, Qin
MicroRNAs(MiRNAs)已被广泛报道可诱导转录后基因沉默，并导致治疗人类疾病的新策略的爆炸性增长。已有研究表明，卒中后血液和脑组织中microRNA-132(miR-132)的表达均发生改变。然而，miR-132对缺血性卒中血脑屏障(BBB)破坏的影响尚未被研究。在这里，我们将研究miR-132对缺血性卒中后血脑屏障通透性的影响，并探讨其潜在的保护机制。8周龄小鼠在大脑中动脉阻塞(MCAO)前2 h侧脑室注射miR-132、antagomir-132或agomir阴性对照(agomir-NC)，然后于MCAO后24 h进行动物行为学检查和脑梗塞体积测量。用Evan‘s蓝渗出量和脑含水量测定血脑屏障通透性和完整性。免疫组化和免疫印迹法检测紧密连接蛋白的表达。检测MIR-132及其靶基因MMP9的表达水平。与对照组相比，外源性MIR-132(AGOMIR-132)治疗减少了脑梗塞体积，减轻了脑水肿，并改善了神经功能。Agomir-132可提高缺血性卒中小鼠脑组织中MIR-132的表达水平，抑制MIR-9mRNA的表达，减少紧密连接蛋白VE-钙粘附素和β-连环素的降解。抑制MMP9对MCAO后脑梗塞体积、脑水肿和紧密连接蛋白表达的保护作用与AGOMIR-132相似。提示miR-132/MMP9轴可能是缺血性卒中血脑屏障保护的一个新的治疗靶点。
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 beta-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.