Inhibiting miR-466b-5p Attenuates Neonatal White Matter Injury by Targeting Lpar1.
Inhibiting miR-466b-5p Attenuates Neonatal White Matter Injury by Targeting Lpar1.
复制标题
DOI：
10.1093/jnen/nlac012
复制
发表时间：
2022-03
影响因子：
3.2
通讯作者：
Dongqiong Xiao;Xiaojuan Su;Xiaoyun Gou;Lingyi Huang;Junjie Ying;Shiping Li;F. Zhao;D. Mu;Y. Qu
中科院分区：
文献类型：
--
作者：
Dongqiong Xiao;Xiaojuan Su;Xiaoyun Gou;Lingyi Huang;Junjie Ying;Shiping Li;F. Zhao;D. Mu;Y. Qu
miR-466 b-5 p在白色物质损伤后的少突胶质前体细胞（OPC）中异常上调。然而，其在新生儿腹泻发病机制中的作用尚不清楚。本研究采用P3大鼠建立新生儿脑缺血缺氧模型。进行生物信息学分析以预测miR-466 b-5 p的可能靶点为Lpar 1。RT-PCR检测miR-466 b-5 p和Lpar 1 mRNA的表达。侧脑室注射miR-466 b-5 p抑制剂，通过免疫荧光染色、免疫印迹和电子显微镜分析OPC分化、凋亡、增殖和髓鞘形成。采用Morris水迷宫实验检测大鼠的行为学表现。检测Sox 10表达和PLP运输，以阐明miR-466 b-5 p调节miR-466 b-5 p发病机制的机制。我们发现，抑制miR-466 b-5 p后，Edg 2蛋白增加，OPC分化和有髓轴突形成增强，大鼠的行为表现得到改善，而OPC增殖和凋亡不受影响。此外，在miR-466 b-5 p抑制后，Sox 10的表达被促进，而PLP运输被减弱。我们的结论是，miR-466 b-5 p参与了调控的cardiovascular发病机制，部分通过Lpar 1/Edg 2/Sox 10和Lpar 1/Edg 2/PLP信号通路。
miR-466b-5p is aberrantly upregulated in oligodendrocyte precursor cells (OPCs) after white matter injury (WMI). However, its roles in neonatal WMI pathogenesis are unknown. In this study, P3 rats were subjected to hypoxia-ischemia to establish a neonatal WMI model. A bioinformatic analysis was conducted to predict the possible target of miR-466b-5p as Lpar1. RT-PCR was performed to validate the expression of miR-466b-5p and Lpar1 mRNA. The miR-466b-5p antagomir was intracerebroventricularly administrated to inhibit miR-466b-5p; OPC differentiation, apoptosis, proliferation, and myelination were analyzed using immunofluorescence staining, western blotting, and electron microscopy. In addition, the behavioral performance of the rats was measured with the Morris water maze test. Sox10 expression and PLP trafficking were examined to elucidate the mechanism by which miR-466b-5p regulates WMI pathogenesis. We found that after inhibiting miR-466b-5p, the Edg2 protein was increased, OPC differentiation and myelinated axon formation were enhanced, and the rats' behavioral performance was improved, whereas OPC proliferation and apoptosis were not affected. Furthermore, the expression of Sox10 was promoted while PLP trafficking was attenuated after miR-466b-5p inhibition. We conclude that miR-466b-5p is involved in the regulation of WMI pathogenesis, partly through the Lpar1/Edg2/Sox10 and Lpar1/Edg2/PLP signaling pathways.