MiR224-5p Inhibitor Restrains Neuronal Apoptosis by Targeting NR4A1 in the Oxygen-Glucose Deprivation (OGD) Model

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Abstract

This study was designed to investigate the molecular mechanism of stroke and to explore the effect of miR-224-5p in hypoxic cortical neurons. Firstly, we established a middle cerebral artery occlusion (MCAO) model with Sprague–Dawley rats. Triphenyltetrazolium chloride (TTC) staining showed the brain infarction of an MCAO rat. Longa scores of rats were significantly increased in 12th, 24th, and 48th hours after MCAO. Then, we found that miR-224-5p was increased after MCAO in rats by qRT-PCR. In order to investigate the effect of miR-224-5p in hypoxic neurons, we established an oxygen-glucose deprivation (OGD) model with cortical neurons. MiR-224-5p was also upregulated in neurons after OGD by qRT-PCR. After transfection of the miR-224-5p inhibitor, the number of neurons in the anti-miR-224-5p group significantly increased ( P < 0.01) in comparison to the anti-NC group. Furthermore, Tuj1 ⁺ (neuronal marker) staining and TUNEL assay (to detect apoptotic cells) were performed in neurons. The survival of neurons in the anti-miR-224-5p group was significantly improved ( P < 0.01), while the apoptosis of neurons in the anti-miR-224-5p group was significantly decreased ( P < 0.01), when compared with that of the anti-NC group. In addition, we predicted that potential target genes of miR-224-5p were nuclear receptor subfamily 4 group A member 1 (NR4A1), interleukin 1 receptor antagonist (IL1RN), and ring finger protein 38 (RNF38) with bioinformatics databases, such as TargetScan, miRDB, miRmap, and miRanda. The result of qRT-PCR confirmed that NR4A1 was significantly decreased after hypoxic injury ( P < 0.01). Meanwhile, luciferase reporter’s assay indicated that NR4A1 was the direct target of miR-224-5p. Compared with the anti-miR-224-5p + siNC group, the number of cortical neurons and the length of the neuron axon in the anti-miR-224-5p + si-NR4A1 group were significantly decreased ( P < 0.01), and the number of neuronal apoptosis in the anti-miR-224-5p + si-NR4A1 group was increased ( P < 0.01). In conclusion, miR-224-5p played a crucial role in hypoxic neuron injury through NR4A1, which might be an important regulatory mechanism in OGD injury of neurons.

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MicroRNAs (miRNAs) are approximately 22 nucleotide RNAs that negatively regulate the expression of protein-coding genes. In a present model of miRNA function in animals, miRNAs that form imperfect duplexes with their targets inhibit protein expression without affecting mRNA levels. Here, we report that in C. elegans, regulation by the let-7 miRNA results in degradation of its lin-41 target mRNA, despite the fact that its 3'UTR regulatory sequences can only partially base-pair with the miRNA. Furthermore, lin-14 and lin-28 are targets of the lin-4 miRNA, and we show that the mRNA levels for these protein-coding genes significantly decrease in response to lin-4 expression. This study reveals that mRNAs containing partial miRNA complementary sites can be targeted for degradation in vivo, raising the possibility that regulation at the level of mRNA stability may be more common than previously appreciated for the miRNA pathway.

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Principles of microRNA regulation of a human cellular signaling network

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MicroRNAs (miRNAs) are endogenous ∼22-nucleotide RNAs, which suppress gene expression by selectively binding to the 3′-noncoding region of specific messenger RNAs through base-pairing. Given the diversity and abundance of miRNA targets, miRNAs appear to functionally interact with various components of many cellular networks. By analyzing the interactions between miRNAs and a human cellular signaling network, we found that miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components such as signaling transcription factors, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components such as ligands. In addition, when an adaptor has potential to recruit more downstream components, these components are more frequently targeted by miRNAs. This work uncovers the principles of miRNA regulation of signal transduction networks and implies a potential function of miRNAs for facilitating robust transitions of cellular response to extracellular signals and maintaining cellular homeostasis.

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NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis.

R. Hanna, C J A Punt, Erica Herrley … (2012)

NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown. Nur77 regulates the development of monocytes, particularly patrolling Ly6C(-) monocytes that may be involved in resolution of inflammation. We sought to determine how absence of nuclear receptor subfamily 4, group A, member 1 (NR4A1) in hematopoietic cells affected atherosclerosis development. Nur77(-/-) chimeric mice on a Ldlr(-/-) background showed a 3-fold increase in atherosclerosis development when fed a Western diet for 20 weeks, despite having a drastic reduction in Ly6C(-) patrolling monocytes. In a second model, mice deficient in both Nur77 and ApoE (ApoE(-/-)Nur77(-/-)) also showed increased atherosclerosis after 11 weeks of Western diet. Atherosclerosis was associated with a significant change in macrophage polarization toward a proinflammatory phenotype, with high expression of tumor necrosis factor-α and nitric oxide and low expression of Arginase-I. Moreover, we found increased expression of toll-like receptor 4 mRNA and protein in Nur77(-/-) macrophages as well as increased phosphorylation of the p65 subunit of NFκB. Inhibition of NFκB activity blocked excess activation of Nur77(-/-) macrophages. We conclude that the absence of Nur77 in monocytes and macrophages results in enhanced toll-like receptor signaling and polarization of macrophages toward a proinflammatory M1 phenotype. Despite having fewer monocytes, Nur77(-/-) mice developed significant atherosclerosis when fed a Western diet. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages and may be important for regulation of atherogenesis.

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Author and article information

Contributors

Ling-Ling Liu: URI : http://loop.frontiersin.org/people/1005871/overview

Shan Qiao: URI : http://loop.frontiersin.org/people/1005876/overview

Mei-Ling Wang: URI : http://loop.frontiersin.org/people/1005880/overview

Huai-Kuan Wu: URI : http://loop.frontiersin.org/people/1005881/overview

Yong-Xin Su: URI : http://loop.frontiersin.org/people/1005882/overview

Ke-Mo Wang: URI : http://loop.frontiersin.org/people/1005884/overview

Xue-Wu Liu: URI : http://loop.frontiersin.org/people/378882/overview

Journal

Journal ID (nlm-ta): Front Neurosci

Journal ID (iso-abbrev): Front Neurosci

Journal ID (publisher-id): Front. Neurosci.

Title: Frontiers in Neuroscience

Publisher: Frontiers Media S.A.

ISSN (Print): 1662-4548

ISSN (Electronic): 1662-453X

Publication date (Electronic): 25 June 2020

Publication date Collection: 2020

Volume: 14

Electronic Location Identifier: 613

Affiliations

[1] ¹Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University , Jinan, China

[2] ²Department of Neurology, Liaocheng People’s Hospital , Liaocheng, China

[3] ³Department of Neurology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated With Shandong First Medical University , Jinan, China

[4] ⁴Department of Neurology, Binzhou Medical University Hospital , Binzhou, China

Author notes

Edited by: Rodrigo Franco, University of Nebraska–Lincoln, United States

Reviewed by: Carmela Matrone, University of Naples Federico II, Italy; Mauricio Alejandro Olguin Albuerne, Université de Genève, Switzerland

*Correspondence: Xue-Wu Liu, snlxw1966@ 123456163.com

^†These authors have contributed equally to this work

This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience

Article

DOI: 10.3389/fnins.2020.00613

PMC ID: 7330102

SO-VID: df6fb600-282d-4470-9ae7-42c55f12ab2a

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 15 January 2020

Date accepted : 18 May 2020

Page count

Figures: 7, Tables: 0, Equations: 0, References: 48, Pages: 12, Words: 0

Funding

Funded by: National Natural Science Foundation of China 10.13039/501100001809

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MiR224-5p Inhibitor Restrains Neuronal Apoptosis by Targeting NR4A1 in the Oxygen-Glucose Deprivation (OGD) Model

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Neuronal Signaling

Most cited references 40

Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation.

Principles of microRNA regulation of a human cellular signaling network

NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis.

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