Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells

Burek, Małgorzata; König, Anna; Lang, Mareike; Fiedler, Jan; Oerter, Sabrina; Roewer, Norbert; Bohnert, Michael; Thal, Serge C.; Blecharz-Lang, Kinga G; Woitzik, Johannes; Thum, Thomas; Förster, Carola

doi:10.1007/s12975-018-0683-2

Cited by 91 publications

(68 citation statements)

References 59 publications

(63 reference statements)

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“…The integrity of the BBB is determined by the endothelial tight junctions and the basal lamina. While endothelial tight junctions are formed by proteins such as claudin, occludin and zonula occluden (ZO), the basal lamina forms the basement membrane of ECM and includes laminin, collagen, and fibronectin [177,178]. Astrocyte-derived factors including angiopoietin-1 (ANG-1) [179][180][181], sonic hedgehog (SHH) [182][183][184][185], glial-derived neurotrophic factor (GDNF) [186][187][188], retinoic acid (RA) [189][190][191], and IGF-1 [192,193] have been demonstrated to promote recovery of the BBB by protecting endothelial cells and/or enhancing tight junction reassembly, via signaling mediated by their receptors, tie-2, patched-1, GDNF receptor alpha-1 and alpha-2, nuclear RA receptor, and IGF-1 receptor, respectively [78,79] (Table.…”

Section: The Bbb Integrity-promoting Effects Of Astrocytesmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

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Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocytederived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporalenvironment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies.

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Section: The Bbb Integrity-promoting Effects Of Astrocytesmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

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“…MiRNAs have been shown to be induced by TBI and therefore may offer therapeutic potential [18]. Previous studies have demonstrated that miR-212 is highly expressed in the brain [19] where it may play a role in synaptic plasticity [20], memory formation [21,22], and blood brain barrier integrity [23]. Meanwhile, this conserved miRNA was shown to be downregulated in Alzheimer's disease (AD), and the tau protein level was increased in the brain of miR-212 knockout mice [24,25].…”

Section: Introductionmentioning

confidence: 99%

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

et al. 2019

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Ferroptosis, a newly discovered form of iron-dependent regulated cell death, has been implicated in traumatic brain injury (TBI). MiR-212-5p has previously been reported to be downregulated in extracellular vesicles following TBI. To investigate whether miR-212-5p is involved in the ferroptotic neuronal death in TBI mice, we first examined the accumulation of malondialdehyde (MDA) and ferrous ion, and the expression of ferroptosis-related molecules at 6 h, 12 h, 24 h, 48 h and 72 h following controlled cortical impact (CCI) in mice. There was a significant upregulation in the expression of Gpx4 and Acsl4 at 6 h, Slc7a11 from 12 h to 72 h, and Nox2 and Sat1 from 6 h to 72 h post injury. Similarly, an upregulation in the expression of Gpx4 at 6 h, Nox2 from 6 h to 72 h, xCT from 12 h to 72 h, and Sat1 at 72 h after CCI was observed at the protein level. Interestingly, MDA and ferrous ion were increased whereas miR-212-5p was decreased in the CCI group compared to the sham group. Furthermore, we found that overexpression of miR-212-5p attenuated ferroptosis while downregulation of miR-212-5p promoted ferroptotic cell death partially by targeting prostaglandin-endoperoxide synthase-2 (Ptgs2) in HT-22 and Neuro-2a cell lines. In addition, administration of miR-212-5p in CCI mice significantly improved learning and spatial memory. Collectively, these findings indicate that miR-212-5p may protect against ferroptotic neuronal death in CCI mice partially by targeting Ptgs2.

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“…While the data on the penetration of miRNA from peripheral tissues to the brain are limited, one can assume that this transfer is highly possible, especially during embryonic development when brain tissue and its compartmentalization is not yet fully formed. Moreover, recent experiments performed in two different rodent models has shown that, in certain conditions, such as during hypoxia, miRNAs actively contribute to an increase in the penetrability of the bloodbrain barrier through the inhibition of genes encoding tight junction proteins (Ma et al, 2017;Burek et al, 2019). The role of prenatal and perinatal factors contributing to the risk of schizophrenia was well documented (Kelly and Murray, 2000;Davis et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

miRNA-Coordinated Schizophrenia Risk Network Cross-Talk With Cardiovascular Repair and Opposed Gliomagenesis

et al. 2020

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Background: Schizophrenia risk genes are widely investigated, but a systemic analysis of miRNAs contributing to schizophrenia is lacking.Methods: Schizophrenia-associated genetic loci profiles were derived from a genomewide association study (GWAS) from the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) dataset. Experimentally confirmed relationships between miRNAs and their target genes were retrieved from a miRTarBase. A competitive gene set association analysis for miRNA-target regulations was conducted by the Multi-marker Analysis of GenoMic Annotation (MAGMA) and further validated by literature-based functional pathway analysis using Pathway Studio. The association between the targets of three miRNAs and schizophrenia was further validated using a GWAS of antipsychotic treatment responses.Results: Three novel schizophrenia-risk miRNAs, namely, miR-208b-3p, miR-208a-3p, and miR-494-5p, and their targetomes converged on calcium voltage-gated channel subunit alpha1 C (CACNA1C) and B-cell lymphoma 2 (BCL2), and these are well-known contributors to schizophrenia. Both miR-208a-3p and miR-208b-3p reduced the expression of the RNA-binding protein Quaking (QKI), whose suppression commonly contributes to demyelination of the neurons and to ischemia/reperfusion injury. On the other hand, both QKI and hsa-miR-494-5p were involved in gliomagenesis. Conclusion:Presented results point at an orchestrating role of miRNAs in the pathophysiology of schizophrenia. The sharing of regulatory networks between schizophrenia and other pathologies may explain higher cardiovascular mortality and lower odds of glioma previously reported in psychiatric patients.

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Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells

Cited by 91 publications

References 59 publications

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

miRNA-Coordinated Schizophrenia Risk Network Cross-Talk With Cardiovascular Repair and Opposed Gliomagenesis

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