MiR-539 Targets MMP-9 to Regulate the Permeability of Blood–Brain Barrier in Ischemia/Reperfusion Injury of Brain

Feng, Fan; Jiao, Yang; Xu, Yuanjie; Guan, Sheng

doi:10.1007/s11064-018-2646-0

Cited by 31 publications

(21 citation statements)

References 29 publications

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“…Meanwhile, a previous report has showed that the expression of miR-539 in the anterior cingulate gyrus decreases after chronic compression injury (8). Importantly, the protective effect of miR-539 on cerebral injury has been documented in a functional study (9). Bioinformatics analysis using the website microRNA.org employed in the present study revealed histone deacetylase 1 (HDAC1) as a putative target of miR-539-5p.…”

Section: Introductionmentioning

confidence: 57%

“…In addition, miRNAs have the capacity to mediate endogenous responses to stroke and may acutely activate novel neuroprotective processes that alleviate ischemic injury (6,26). For instance, miR-539 significantly attenuates blood-brain barrier permeability by targeting matrix metalloproteinase-9 (MMP-9), thus alleviating cerebral ischemia/reperfusion injury (9). miR-539 also mediates mitochondrial fission and apoptosis by targeting prohibitin 2 (28).…”

Section: Introductionmentioning

confidence: 99%

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Overexpressed microRNA-539-5p inhibits inflammatory response of neurons to impede the progression of cerebral ischemic injury by histone deacetylase 1

Xue

Liu

Shi

et al. 2020

American Journal of Physiology-Cell Physiology

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Several microRNAs (miRNAs or miRs) regulate cerebral ischemic injury outcomes; however, little is known about the role of miR-539-5p during cerebral ischemic injury or the post-ischemic state. Cerebral ischemic injury was modeled in vitro by exposing human cortical neurons to oxygen-glucose deprivation (OGD) and in vivo by occluding the middle cerebral artery (MCAO) in a rat model. The effects of miR-539-5p, histone deacetylase 1 (HDAC1), and early growth response 2 (EGR2) on cerebral ischemia were investigated using gain- and loss-of-function experiments. We identified changes in miR-539-5p, HDAC1, EGR2, and phosphorylated c-Jun N-terminal kinase (JNK). The interaction among miR-539-5p, HDAC1 and EGR2 was determined by dual luciferase reporter gene assay, chromatin immunoprecipitation and co-immunoprecipitation. We also investigated the effects on cell viability and apoptosis, changes in inflammatory cytokine expression and spatial memory on MCAO rats. miR-539-5p and EGR2 were poorly expressed, while HDAC1 was highly expressed in OGD-treated HCN-2 cells. miR-539-5p targeted HDAC1, while HDAC1 prevented acetylation of EGR2 resulting in its downregulation and subsequent activation of the JNK pathway. Overexpression of miR-539-5p or EGR2 or silencing HDAC1 improved viability and reduced apoptosis of OGD-treated HCN-2 cells in vitro. Furthermore, overexpression of miR-539-5p improved spatial memory, while decreasing cell apoptosis and inflammation in MCAO rats. Collectively, these data suggest that miR-539-5p targets HDAC1 to upregulate EGR2, thus blocking the JNK signaling pathway, by which cerebral ischemic injury is alleviated.

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Section: Introductionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Overexpressed microRNA-539-5p inhibits inflammatory response of neurons to impede the progression of cerebral ischemic injury by histone deacetylase 1

Xue

Liu

Shi

et al. 2020

American Journal of Physiology-Cell Physiology

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“…In response to cerebral ischemia, astrocytes undergo hyperplasia and metabolic reserve enhancement and delayed apoptosis is observed in neurons [28][29][30]. Aberrant miRNA expression levels have been correlated with models of cerebral ischemia injury [31][32][33]. MiR-19a-3p has been found to highly correlate with the development of a variety of cancers, especially in astrocytoma [20].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

Wang

Liu

et al. 2019

Cell Mol Biol Lett

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Background: Accumulating evidence has shown that altered microRNA (miR) modulation is implicated in the pathologies of ischemic stroke. However, it is unclear whether and how hsa-miR-19a-3p mediates cerebral ischemic injury. Herein, we investigated the functional role of miR-19a-3p in cerebral ischemic injury and explored its underlying regulatory mechanism. Methods: In vivo ischemic/reperfusion (I/R) neuronal injury and in vitro oxygenglucose deprivation (OGD) were established. Expression of miR-19a-3p was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Glucose uptake, lactate production, and apoptosis were determined. ADIPOR2 was predicted as a target of miR-19a-3p in silico and experimentally validated by qRT-PCR, Western blot analysis and luciferase assay assays. Results: MiR-19a expression was significantly downregulated and upregulated in rat neurons and astrocytes, respectively (P < 0.01). A significantly elevated level of miR-19a-3p was found in I/R and OGD models in comparison to sham/control groups (P < 0.01). Expression of the glycolysis enzyme markers LDHA, PKM2, HK2, Glut1 and PDK1, apoptosis-related factors levels, apoptosis, glucose uptake, and lactate production were significantly repressed by both I/R and OGD (P < 0.01 in each case). Moreover, miR-19a-3p mimic aggravated, while miR-19a-3p inhibitor alleviated, the above observations. Adipor2 was predicted and confirmed to be a direct target of miR-19a. Furthermore, restoration of Adipor2 reversed miR-19a-3p-induced effects. Conclusions: Collectively, our results indicate that elevated miR-19a-3p mediates cerebral ischemic injury by targeting ADIPOR2. MiR-19a-3p attenuation thus might offer hope of a novel therapeutic target for ischemic stroke injury treatment.

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“…Agomir-132 (exogenous miR-132) suppressed the transcript of MMP-9 and decreased the degradation of VE-cadherin in a mouse model of ischemic stroke [ 51 ]. Another study showed increased miR-539 expression in the brain tissue in rats after ischemia, which directly inhibits MMP-9 expression and protects ECs from oxygen-glucose deprivation (OGD)-induced EC monolayer hyperpermeability [ 52 ]. Moreover, other miRNAs have been found to directly target signaling pathways that regulate the expression, distribution and degradation of the junctional proteins.…”

Section: Potential Role Of Mirnas In Bbb Disruptionmentioning

confidence: 99%

MicroRNAs in the Blood-Brain Barrier in Hypoxic-Ischemic Brain Injury

Shen

2020

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: Hypoxic-ischemic (HI) brain injury is a leading cause of acute mortality and chronic disability in newborns. Current evidence shows that cerebral microvascular response and compromised blood-brain barrier (BBB) integrity occur rapidly and could primarily be responsible for the brain injury observed in many infants with HI brain injury. MicroRNAs (miRNAs) are a type of highly conserved non-coding RNAs (ncRNAs), which consist of 21-25 nucleotides in length and usually lead to suppression of target gene expression. Growing evidence has revealed that brain-enriched miRNAs act as versatile regulators of BBB dysfunctions in various neurological disorders including neonatal HI brain injury. In the present review, we summarize the current findings regarding the role of miRNAs in BBB impairment after hypoxia/ischemia brain injury. Specifically, we focus on the recent progress of miRNAs in the pathologies of neonatal HI brain injury. These findings can not only deepen our understanding of the role of miRNAs in BBB impairment in HI brain injury, but also provide insight into the development of new therapeutic strategies for preservation of BBB integrity under pathological conditions.

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MiR-539 Targets MMP-9 to Regulate the Permeability of Blood–Brain Barrier in Ischemia/Reperfusion Injury of Brain

Cited by 31 publications

References 29 publications

Overexpressed microRNA-539-5p inhibits inflammatory response of neurons to impede the progression of cerebral ischemic injury by histone deacetylase 1

Overexpressed microRNA-539-5p inhibits inflammatory response of neurons to impede the progression of cerebral ischemic injury by histone deacetylase 1

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

MicroRNAs in the Blood-Brain Barrier in Hypoxic-Ischemic Brain Injury

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