Zhao Zhenying, Lu Zhiqiang, Sun Xiuying, Zhao Tianhong, Zhang Jihong, Zhou Cunxia, Zheng Xiaohui, Zhang Huijuan, Shi Guiling
Department of Pharmacy, Tianjin Union Medical Center, Tianjin, China; School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
School of Pharmacy, Tianjin University, Tianjin, China.
J Stroke Cerebrovasc Dis. 2017 Jul;26(7):1622-1634. doi: 10.1016/j.jstrokecerebrovasdis.2017.02.017. Epub 2017 Apr 21.
This study aims to investigate the molecular mechanism of injury development in the cortex and the striatum after cerebral ischemia/reperfusion (I/R).
Gene expression data (GSE23160) in the cortex and the striatum of an intraluminal middle cerebral artery occlusion-I/R mouse model (N = 12) and sham controls (N = 4) were downloaded from the Gene Expression Omnibus. Limma package was used to identify the differentially expressed genes (DEGs) between the I/R (2, 8, and 24 hours) and control groups. Correlation analysis was then performed to identify the highly correlated differentially expressed genes (HCDEGs). STRING and Cytoscape software were used to construct a protein-protein interaction (PPI) network of HCDEGs. Furthermore, Venny 2.0 was used to identify common overlapped DEGs whose transcription factors (TFs) were predicted using iRegulon in Cytoscape.
For the cortex and the striatum, 2295 and 2282 DEGs were respectively identified between the I/R group and the controls, and were classified into 3 and 2 correlation modules. For each module, a PPI network was constructed, and Toll-like receptor 2 (Tlr2, degree = 25), interleukin 1β (Il1b, degree = 21), and heme oxygenase-1 (Hmox1, degree = 17) had high connective degrees. Furthermore, 29 common overlapped DEGs were found across time and tissue, which might be targeted by 13 TFs. Especially, Tlr2, Il1b, and Hmox1 were targeted by myeloblastosis protein (Myb, target count = 16) and FBJ osteosarcoma protein (Fos, target count = 15). Moreover, plasminogen activator urokinase receptor (Plaur) was targeted by Fos, and it was an HCDEG in correlation modules of both cortex and striatum. Upregulation of Tlr2, Il1b, Hmox1, and Plaur in I/R injury was confirmed using quantitative polymerase chain reaction and immunohistochemical staining.
Tlr2, Il1b, Hmox1, and Plaur regulated by Myb and Fos might participate in cortex and striatum injury after cerebral I/R.
本研究旨在探讨脑缺血/再灌注（I/R）后皮质和纹状体损伤发展的分子机制。
从基因表达综合数据库下载大脑中动脉腔内闭塞-I/R小鼠模型（N = 12）和假手术对照组（N = 4）的皮质和纹状体中的基因表达数据（GSE23160）。使用Limma软件包鉴定I/R组（2、8和24小时）与对照组之间的差异表达基因（DEG）。然后进行相关性分析以鉴定高度相关的差异表达基因（HCDEG）。使用STRING和Cytoscape软件构建HCDEG的蛋白质-蛋白质相互作用（PPI）网络。此外，使用Venny 2.0鉴定共同重叠的DEG，其转录因子（TF）在Cytoscape中使用iRegulon进行预测。
对于皮质和纹状体，I/R组与对照组之间分别鉴定出2295个和2282个DEG，并分为3个和2个相关模块。针对每个模块构建了PPI网络，Toll样受体2（Tlr2，度 = 25）、白细胞介素1β（Il1b，度 = 21）和血红素加氧酶-1（Hmox1，度 = 17）具有高连接度。此外，在不同时间和组织中发现了29个共同重叠的DEG，其可能由13个TF靶向。特别是，Tlr2、Il1b和Hmox1由成髓细胞白血病蛋白（Myb，靶向计数 = 16）和FBJ骨肉瘤蛋白（Fos，靶向计数 = 15）靶向。此外，纤溶酶原激活物尿激酶受体（Plaur）由Fos靶向，并且它是皮质和纹状体相关模块中的HCDEG。使用定量聚合酶链反应和免疫组织化学染色证实了I/R损伤中Tlr2、Il1b、Hmox1和Plaur的上调。
由Myb和Fos调节的Tlr2、Il1b、Hmox1和Plaur可能参与脑I/R后的皮质和纹状体损伤。
