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Upregulated LINC00319 aggravates neuronal injury induced by oxygen-glucose deprivation via modulating miR-200a-3p.

ABSTRACT: Ischemic stroke is one of the main causes of physical disability and mortality worldwide. Long non-coding RNAs (lncRNAs) are reported to be dysregulated in various biological progressions and serve important roles in pathological processes of cerebral ischemia. However, their biological actions and potential mechanisms in the progression of ischemic stroke remain unknown. The present study aimed to investigate the functions of LINC00319 on ischemic brain injury. It was identified that LINC00319 was significantly upregulated in the Gene Expression Omnibus profile of ischemic stroke. Furthermore, LINC00319 overexpression elevated caspase-3 activity and increased the apoptotic rate of neuronal cells, as well as decreased cell viability and glucose uptake. It was also demonstrated that LINC00319 participated in oxygen-glucose deprivation (OGD)-induced cerebral ischemic injury. LINC00319 could competitively bind with microRNA (miR)-200a-3p and decrease its expression. Moreover, miR-200a-3p could partly offset the negative effects of LINC00319 overexpression on neuronal injury caused by OGD. Collectively, the present results suggested that LINC00319 promoted apoptosis and aggravated neuronal injury induced by OGD by regulating miR-200a-3p, which may be important for ischemic stroke treatment.

SUBMITTER: Yang H

PROVIDER: S-EPMC8210224 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Neuronal apoptosis is a major pathological hallmark of the neonatal hypoxic-ischemic brain damage (HIBD); however, the role of miR-7a-2-3p in the regulation of HIBD remains unknown. The purpose of this study was to explore the possible roles of miR-7a-2-3p in brain injury using a hypoxia-ischemia model in rats and oxygen-glucose deprivation (OGD) model in vitro. Firstly, we established the hypoxia-ischemia (HI) model and verified the model using Zea Longa scores and MRI in rats. Next, the changes of miR-7a-2-3p were screened in the ischemic cortex of neonatal rats by qRT-PCR at 12, 48, and 96 h after HIBD. We have found that the expression of miR-7a-2-3p in the HI rats decreased significantly, compared with the sham group (P < 0.01). Then, we established the OGD model in PC12 cells, SH-SY5Y cells and primary cortical neurons in vitro and qRT-PCR was used to confirm the changes of miR-7a-2-3p in these cells after the OGD. In order to determine the function of miR-7a-2-3p, PC12 cells, SH-SY5Y cells and rat primary cortical neurons were randomly divided into normal, OGD, mimic negative control (mimic-NC) and miR-7a-2-3p groups. Then, Tuj1+ (neuronal marker) staining, TUNEL assay (to detect apoptotic cells) and MTT assay (to investigate cell viability) were performed. We have found that the number of PC12 cells, SH-SY5Y cells and cortical neurons in the miR-7a-2-3p groups increased significantly (P < 0.01) in comparison to the OGD groups. The survival of cortical neurons in the miR-7a-2-3p group was improved markedly (P < 0.01), while the apoptosis of neurons in the miR-7a-2-3p group was significantly decreased (P < 0.01), compared with the normal group. Lastly, we investigated the target genes of miR-7a-2-3p by using the prediction databases (miRDB, TargetScan, miRWalk, and miRmap) and verified the target genes with qRT-PCR in the HI rats. Bioinformatics prediction showed that Vimentin (VIM), pleiomorphic adenoma gene 1(PLAG1), dual specificity phosphatase 10 (DUSP10), NAD(P)H dehydrogenase, quinone 1 (NQO1) and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) might be the targets of miR-7a-2-3p and the qRT-PCR confirmed that VIM increased in the HI rats (P < 0.01). In conclusion, miR-7a-2-3p plays a crucial role in the hypoxic-ischemic injury, and is associated with regulation of VIM.

Project description:BackgroundCerebral stroke induces neuronal dysfunction as a consequence of neuronal morphology changes. Emerging evidence suggests that microRNAs (miRNAs) may play an important role in regulating dysfunction in stroke, yet there are still few studies examining the association between whole blood miRNAs and neuronal morphology. The present study aimed to ascertain the potential roles and mechanisms of action of miR-130a-3p in ischemic stroke.MethodsThe miRNA datasets of peripheral serum in the GEO database and the mRNA datasets of the human brain after ischemia were analyzed to identify differentially expressed RNAs, and their functions were verified in cultured neurons in vitro. Furthermore, the target gene was validated by dual-luciferase reporter assay, RT-PCR, Western blot, and immunofluorescence experiments. The identified miRNA was further verified by the OGD test to restore neuronal changes after ischemia through APP.ResultsThe expression of whole blood miR-130a-3p was found significantly lower in participants with ischemic stroke than in controls by analyzing expression profiling datasets of cerebral ischemia stroke obtained from the Gene Expression Omnibus (GEO) DataSets portal, which was confirmed in the MCAO model in mice. Furthermore, GO analysis showed that miR-130a-3p might directly affect neuronal function. Indeed, we demonstrated that miR-130a-3p played a central role in the inhibition of dendritic morphogenesis and in the growth of dendritic spines in vitro. We also confirmed that miR-130a-3p could regulate the expression of APP by luciferase reporter assay, RT-PCR, Western blot, and immunofluorescence experiments, which were consistent with the bioinformatic analysis. Last but not least, we also demonstrated that reducing miR-130a-3p expression partially rescued neuronal morphological changes after OGD in vitro.ConclusionmiR-130a-3p is a potential biomarker of cerebral stroke, can affect neuronal morphology through APP, and promote the repair of neurons by promoting APP expression after cerebral ischemia.

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Upregulated LINC00319 aggravates neuronal injury induced by oxygen-glucose deprivation via modulating miR-200a-3p.

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