Bai Ying, Zhang Yuan, Hua Jun, Yang Xiangyu, Zhang Xiaotian, Duan Ming, Zhu Xinjian, Huang Wenhui, Chao Jie, Zhou Rongbin, Hu Gang, Yao Honghong
Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, China.
Sci Rep. 2016 Oct 21;6:35642. doi: 10.1038/srep35642.
MicroRNA-143 (miR-143) plays a critical role in various cellular processes; however, the role of miR-143 in the maintenance of blood-brain barrier (BBB) integrity remains poorly defined. Silencing miR-143 in a genetic animal model or via an anti-miR-143 lentivirus prevented the BBB damage induced by methamphetamine. miR-143, which targets p53 unregulated modulator of apoptosis (PUMA), increased the permeability of human brain endothelial cells and concomitantly decreased the expression of tight junction proteins (TJPs). Silencing miR-143 increased the expression of TJPs and protected the BBB integrity against the effects of methamphetamine treatment. PUMA overexpression increased the TJP expression through a mechanism that involved the NF-κB and p53 transcription factor pathways. Mechanistically, methamphetamine mediated up-regulation of miR-143 via sigma-1 receptor with sequential activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3' kinase (PI3K)/Akt and STAT3 pathways. These results indicated that silencing miR-143 could provide a novel therapeutic strategy for BBB damage-related vascular dysfunction.
微小RNA - 143（miR - 143）在多种细胞过程中发挥关键作用；然而，miR - 143在维持血脑屏障（BBB）完整性方面的作用仍不清楚。在基因动物模型中或通过抗miR - 143慢病毒沉默miR - 143可预防甲基苯丙胺诱导的血脑屏障损伤。靶向凋亡调节蛋白p53非调节因子（PUMA）的miR - 143增加了人脑内皮细胞的通透性，并同时降低了紧密连接蛋白（TJPs）的表达。沉默miR - 143可增加TJPs的表达，并保护血脑屏障完整性免受甲基苯丙胺治疗的影响。PUMA过表达通过涉及核因子κB（NF - κB）和p5３转录因子途径的机制增加了TJPs的表达。从机制上讲，甲基苯丙胺通过σ-1受体介导miR - 143的上调，并依次激活丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3'激酶（PI3K）/蛋白激酶B（Akt）以及信号转导子和转录激活子3（STAT3）途径。这些结果表明，沉默miR - 143可为血脑屏障损伤相关的血管功能障碍提供一种新的治疗策略。
