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microRNA-381-3p Confers Protection Against Ischemic Stroke Through Promoting Angiogenesis and Inhibiting Inflammation by Suppressing Cebpb and Map3k8

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Abstract

Ischemic stroke is a serious disease with limited prevention methods, and various genes and microRNAs (miRNAs) have been found to be dysregulated in the pathogenesis of this disease. This study aims to explore the potential role of miR-381-3p in ischemic stroke, along with its underlying mechanism. A mouse model of ischemic stroke was developed using middle cerebral artery occlusion. Next, the expression of mitogen-activated protein kinase kinase kinase 8 (Map3k8) and CCAAT enhancer binding protein beta (Cebpb) was determined by RT-qPCR. Gain- and loss-of-function approaches were applied to analyze the effects of miR-381-3p, Cebpb and Map3k8 on the biological functions of endothelial progenitor cells (EPCs) with the involvement of the tumor necrosis factor-α (TNF-α) signaling pathway. In addition, dual luciferase reporter gene assay was performed for the analysis of the relationship among miR-381-3p, Map3k8 and Cebpb. Further, rescue experiment was performed with the help of JNK/p38 specific agonist, Anisomycin. Map3k8 and Cebpb were highly expressed in ischemic stroke. Loss-of-function of Map3k8 or Cebpb in EPCs contributed to accelerated proliferation, migration and angiogenesis of EPCs. Next, miR-381-3p downregulated the expression of its two target genes, Map3k8 and Cebpb. miR-381-3p overexpression promoted angiogenesis of EPCs, and inhibited inflammation, which could be reversed by restoration of Map3k8 or Cebpb. Additionally, silencing Map3k8 or Cebpb inhibited the activation of TNF-α signaling pathway. Furthermore, Anisomycin treatment could enhance inflammation and inhibit angiogenesis. Taken together, miR-381-3p downregulates Map3k8 and Cebpb to protect against ischemic stroke, broadening our understanding of the pathogenesis of ischemic stroke.

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Data Availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgement

We would like to give our sincere appreciation to the reviewers for their helpful comments on this article.

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  1. Department of Neurology, The Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan East Road, Huanggu District, Shenyang, 110032, Liaoning, People’s Republic of China

    Jie Li, Hui Lv & Yuqin Che

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  1. Jie Li
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  2. Hui Lv
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Contributions

JL and HL designed the study. HL and YC collated the data, carried out data analyses and produced the initial draft of the manuscript. JL and HL contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Yuqin Che.

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Li, J., Lv, H. & Che, Y. microRNA-381-3p Confers Protection Against Ischemic Stroke Through Promoting Angiogenesis and Inhibiting Inflammation by Suppressing Cebpb and Map3k8. Cell Mol Neurobiol 40, 1307–1319 (2020). https://doi.org/10.1007/s10571-020-00815-4

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