Upregulation of miR-199a-5p Protects Spinal Cord Against Ischemia/Reperfusion-Induced Injury via Downregulation of ECE1 in Rat

Bao, Ning; Fang, Bo; Lv, Huang-Wei; Jiang, Yanhua; Chen, Fengshou; Wang, Zhilin; Ma, Hong

doi:10.1007/s10571-018-0597-2

Cited by 50 publications

(43 citation statements)

References 49 publications

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“…Thus, it participates in the metabolism of α-synuclein that could contribute to the development and progression of dementia with Lewy bodies. It is interesting to note that miR-199a-5p, which negatively regulated ECE1, and silencing the ECE1 gene are protected the rat spinal cord injury after ischemia-reperfusion (Bao et al 2018). Therefore, we demonstrated that miR-199a-5p might protect the spinal cord against ischemia-reperfusion-induced injury by negatively regulating the ECE1.…”

mentioning

confidence: 65%

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells

Minchenko

Tsymbal

Riabovol

et al. 2019

Endocrine Regulations

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Objective. The aim of the present investigation was to study the effect of hypoxia on the expression of genes encoding endothelin-1 (EDN1) and its cognate receptors (EDNRA and EDNRB) as well as endothelin converting enzyme 1 (ECE1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioma growth through ERN1 and hypoxia.Methods. The expression level of EDN1, EDNRA, EDNRB, and ECE1 genes as well as micro-RNA miR-19, miR-96, and miR-206 was studied in control and ERN1 knockdown U87 glioma cells under hypoxia by quantitative polymerase chain reaction.Results. It was shown that the expression level of EDN1, EDNRA, EDNRB, and ECE1 genes was up-regulated in ERN1 knockdown glioma cells in comparison with the control glioma cells, being more significant for endothelin-1. We also observed down-regulation of microRNA miR-206, miR-96, and miR-19a, which have specific binding sites in mRNA EDN1, EDNRA, and EDNRB, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Furthermore, inhibition of ERN1 endoribonuclease lead to up-regulation of EDNRA and ECE1 gene expressions and down-regulation of the expression level of EDN1 and EDNRB genes in glioma cells. Thus, the expression of EDNRA and ECE1 genes is regulated by ERN1 endoribonuclease, but EDN1 and EDNRB genes preferentially by ERN1 protein kinase. We have also shown that hypoxia enhanced the expression of EDN1, EDNRA, and ECE1 genes and that knockdown of ERN1 signaling enzyme function significantly modified the response of all studied gene expressions to hypoxia. Thus, effect of hypoxia on the expression level of EDN1 and ECE1 genes was significantly or completely reduced in ERN1 knockdown glioma cells since the expression of EDNRA gene was down-regulated under hypoxia. Moreover, hypoxia is induced the expression of EDNRB gene in ERN1 knockdown glioma cells.Conclusions. Results of this investigation demonstrate that ERN1 knockdown significantly increased the expression of endothelin-1 and its receptors as well as ECE1 genes by different mechanisms and that all studied gene expressions were sensitive to hypoxia. It is possible that hypoxic regulation of the expression of these genes is a result of complex interaction of variable ERN1 related transcription and regulatory factors with HIF1A and possibly contributed to the control of glioma growth.

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confidence: 65%

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells

Minchenko

Tsymbal

Riabovol

et al. 2019

Endocrine Regulations

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“…Lv et al reported that miR-199a can be sequestered by lncRNA-Map2k4, which subsequently promotes FGF1 expression and mouse spinal cord neuron growth 35 . Bao et al revealed that miR-199a-5p might protect the spinal cord against I/R-induced injury by negatively regulating ECE1 in rats 36 . These findings indicated that miR-199a plays different roles in various disease models.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of sh-miR-199a-5p-Modified Olfactory Ensheathing Cells Promotes the Functional Recovery in Rats with Contusive Spinal Cord Injury

Gao

Zhao

et al. 2020

Cell Transplant

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MicroRNAs (miRNAs) function as gene expression switches, and participate in diverse pathophysiological processes of spinal cord injury (SCI). Olfactory ensheathing cells (OECs) can alleviate pathological injury and facilitate functional recovery after SCI. However, the mechanisms by which OECs restore function are not well understood. This study aims to determine whether silencing miR-199a-5p would enhance the beneficial effects of the OECs. In this study, we measured miR-199a-5p levels in rat spinal cords with and without injury, with and without OEC transplants. Then, we transfected OECs with the sh-miR-199a-5p lentiviral vector to reduce miR-199a-5p expression and determined the effects of these OECs in SCI rats by Basso–Beattie–Bresnahan (BBB) locomotor scores, diffusion tensor imaging (DTI), and histological methods. We used western blotting to measure protein levels of Slit1, Robo2, and srGAP2. Finally, we used the dual-luciferase reporter assay to assess the relationship between miR-199-5p and Slit1, Robo2, and srGAP2 expression. We found that SCI significantly increased miR-199a-5p levels ( P < 0.05), and OEC transplants significantly reduced miR-199a-5p expression ( P < 0.05). Knockdown of miR-199a-5p in OECs had a better therapeutic effect on SCI rats, indicated by higher BBB scores and fractional anisotropy values on DTI, as well as histological findings. Reducing miR-199a-5p levels in transplanted OECs markedly increased spinal cord protein levels of Slit1, Robo2, and srGAP2. Our results demonstrated that transplantation of sh-miR-199a-5p-modified OECs promoted functional recovery in SCI rats, suggesting that miR-199a-5p knockdown was more beneficial to the therapeutic effects of OEC transplants. These findings provided new insights into miRNAs-mediated therapeutic mechanisms of OECs, which helps us to develop therapeutic strategies based on miRNAs and optimize cell therapy for SCI.

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“…We Several miRNAs are aberrantly expressed during spinal cord IR, and may act as protective or pathological factors. For example, increased levels of miR-27a attenuated IR-related damage in the spinal cord by targeting the TLR4 inflammatory pathway [24], while miR-199a-5p also exerted a protective effect by blocking ECE1-mediated apoptosis signaling [28]. In contrast, inhibiting miRNA-124 protected rats against spinal cord IR by inducing mitophagy [29].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Long Noncoding RNA TUG1 Attenuate MTDH /NF-κB/IL-1β mediated inflammatory damage via Targeting miR-29b-1-5p After Spinal cord ischemia reperfusion in rats

Jia

Fang

et al. 2020

Preprint

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Background: Spinal cord ischemia reperfusion (IR) is associated with an inflammatory response. The long non-coding RNA (lncRNA) taurine upregulated gene 1 (TUG1) and microRNA-29b (miR-29b) family are frequently dysregulated in neuro-ischemic diseases. However, their potential roles in spinal cord IR injury (IR) are unknown. Methods: A spinal cord IR model was established in rats by14-minute occlusion of aortic arch. The aberrant miRNAs were identified by microarray analysis, and qRT-PCR was used to validate the lncRNA and microRNA levels. The motor function of the differentially-treated animals was assessed by Tarlov scores, and the leakage of Blood-spinal cord barrier (BSCB) was measured in terms of the extravasation of Evans blue (EB) dye. The expression levels of different proteins were analyzed by Western blotting and immunofluorescence. The interaction between TUG1 and miR-29b-1-5p, TRIL and miR-29b-1-5p, and MTDH and miR-29b-1-5p were determined using bioinformatics programs and the dual-luciferase reporter assay. Results: MiR-29b-1-5p was significantly downregulated and TUG1 was upregulated in the spinal cord of rats after IR. In addition, TRIL and MTDH protein levels were also significantly increased after IR. MTDH was predicted as a target of miR-29b-1-5p and its knockdown downregulated NF-κB and IL-1β levels. In addition, a direct interaction was observed between TUG1 and miR-29b-1-5p, and knocking down TUG1 upregulated the miRNA. Furthermore, overexpression of miR-29b-1-5p or TUG1 knockdown alleviated BSCB leakage and improved hind-limb motor function, and downregulated MTDH and its downstream pro-inflammatory cytokines. Suppression of miR-29b-1-5p reversed the neuroprotective effect of TUG1 knockdown, restored the levels of MTDH/ NF-κB/IL-1β and activated astrocytes. Conclusion: Downregulation of TUG1 alleviated MTDH/NF-κB/IL-1β pathway-mediated inflammatory damage after IR by targeting miR-29b-1-5p. Keywords: Spinal cord ischemia reperfusion injury, Neuroinflammation, Blood-spinal cord barrier, Astrocytes, TUG1, miR-29b-1-5p, MTDH

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Upregulation of miR-199a-5p Protects Spinal Cord Against Ischemia/Reperfusion-Induced Injury via Downregulation of ECE1 in Rat

Cited by 50 publications

References 49 publications

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells

Hypoxic regulation of EDN1, EDNRA, EDNRB, and ECE1 gene expressions in ERN1 knockdown U87 glioma cells

Transplantation of sh-miR-199a-5p-Modified Olfactory Ensheathing Cells Promotes the Functional Recovery in Rats with Contusive Spinal Cord Injury

Downregulation of Long Noncoding RNA TUG1 Attenuate MTDH /NF-κB/IL-1β mediated inflammatory damage via Targeting miR-29b-1-5p After Spinal cord ischemia reperfusion in rats

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