microRNA-381-3p Confers Protection Against Ischemic Stroke Through Promoting Angiogenesis and Inhibiting Inflammation by
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ORIGINAL RESEARCH
microRNA‑381‑3p Confers Protection Against Ischemic Stroke Through Promoting Angiogenesis and Inhibiting Inflammation by Suppressing Cebpb and Map3k8 Jie Li1 · Hui Lv1 · Yuqin Che1 Received: 20 August 2019 / Accepted: 16 February 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Ischemic stroke · microRNA-381-3p · CCAAT enhancer binding protein beta · Mitogen-activated protein kinase kinase kinase 8 · Angiogenesis · TNF-α signaling pathway
Introduction The increased absolute number of individuals suffering from or remaining disabled from stroke causes a socioeconomic burden on families and our society around the world (Feigin et al. 2017). Ischemic stroke accounts for approximately 80% of all cases of stroke (Boehme et al. 2017). The currently applied therapeutic approaches for ischemic stroke, including endovascular therapy and dual antiplatelet therapy have achieved effective outcomes (Hankey 2013; Goyal et al. * Yuqin Che [email protected] 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
2015). Moreover, a recently conducted study has proposed pharmacolo
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