Up-regulating lncRNA OIP5-AS1 protects neuron injury against cerebral hypoxia-ischemia induced inflammation and oxidative stress in microglia/macrophage through activating CTRP3 via sponging miR-186-5p

doi:10.1016/j.intimp.2020.107339

International Immunopharmacology

Volume 92, March 2021, 107339

https://doi.org/10.1016/j.intimp.2020.107339 Get rights and content

Highlights

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OIP5-AS1 is down-regulated in IR patients, tMCAO/R rat models, and OGD/R treated microglia.
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OIP5-AS1 depresses inflammation and oxidative stress in tMCAO/R and OGD/R.
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OIP5-AS1 exerts it role through the miR-186-5p/CTRP3 axis.

Abstract

Background

Inflammation and oxidative stress is closely associated with the development of ischemic brain stroke. Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1), a novel identified long non-coding RNA (lncRNA), has been suggested to play an important role in the development of many types of human cancers. However, the functional involvement of OIP5-AS1 in ischemic stroke is still unknown.

Methods

Quantitative real-time polymerase chain reaction and /or western blot were conducted to determine the expression profiles of OIP5-AS1, C1q/TNF-related protein 3 (CTRP3) and miR-186-5p in the serum of stroke patients, as well as in the ischemic penumbra of rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and microglial cells treated with oxygen glucose deprivation/re-oxygenation (OGD/R). Upon selective regulation of OIP5-AS1 and miR-186-5p, the inflammation and oxidative stress responses in microglia/macrophage as well as neurologic functions in MCAO/R rats were detected. Furthermore, the interactions between OIP5-AS1 and miR-186-5p, miR-186-5p and CTRP3 were investigated by RNA immunoprecipitation (RIP) assay, luciferase report assay and bioinformation anaylsis.

Results

We observed markedly increased infarct volume, neuronal apoptosis, inflammation and oxidative stress responses in the infarcted lesions of MCAO/R rats, in line with down-regulated levels of OIP5-AS1 and CTRP3 while up-regulated miR-186-5p. Functional studies demonstrated that up-regulation of OIP5-AS1 attenuated infarct volume, neuronal apoptosis, microglia/macrophage inflammation and oxidative stress responses induced by MCAO/R or OGD/R. In terms of mechanism, we revealed that OIP5-AS1-miR-186-5p-CTRP3 axis played a vital role in modulating microglia/macrophage activation and neuronal apoptosis.

Conclusion

Up-regulating lncRNA OIP5-AS1 protects neuron injury against MCAO/R induced inflammation and oxidative stress in microglia/macrophage through activating CTRP3 via sponging miR-186-5p.

Introduction

Ischemic stroke, which involves two phases, ischemia and reperfusion, is one of the prevailing contributors of death and long-term disability worldwide [1], [2], [3]. Particularly, the inflammatory response and oxidative stress brought by microglia after ischemia/reperfusion are essential factors of neuron death and brain damage [4], [5], [6]. Therefore, it is highly expected that the study of the molecular mechanisms in ischemic stroke would provide a new treatment idea for it.

Long non-coding RNA (lncRNA) brings into play the unique function of different neurological diseases by regulating multiple downstream targets (such as chromatin, RNA, and proteins). Taking lncRNA TUG1 (taurine-up-regulated gene 1) as an example, its downregulation reduced the apoptosis of MA-C cells exposed to OGD/R injury, and knocking down TUG1 alleviated the infarction area and cell apoptosis in I/R mouse brains in vivo [7]. In cerebral infarction, lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) expression level was notably increased, and knocking down lncRNA ANRIL remarkably reduced CI-induced neurological deficits and CI area [8]. OIP5-AS1, a long non-coding RNA on human chromosome 15q15.1 with a length of 8844 bp, has the opposite transcription direction to OIP5 [9]. Researches have shown that lncRNA OIP5-AS1 is a crucial regulator in certain cancers [10], [11]. Interestingly, OIP5-AS1 also exerts prominent roles on non-tumor diseases such as osteoblast differentiation [12], atherosclerosis [13], osteoarthritis [14], suggesting that OIP5-AS1 plays a role in modulating inflammatory reactions in those diseases. Interestingly, a recent study found that the microangiopathy in diabetic mouse was markedly aggravated with the downregulation of OIP5-AS1, accompanied with neurological deficits [15]. Nevertheless, the mechanism of OIP5-AS1 in ischemic stroke is still unclear.

It is testified that microRNAs (miRNAs), another class of non-coding RNAs, take part in the inflammatory mechanisms of cerebral ischemia [16]. For example, miR-183 regulated microglial activation in rats caused by cerebral ischemia-reperfusion injury by restraining the nuclear factor kappaB (NF-κB) signal pathway [17]. The down-regulation of miR-217 targets the sirtuin 1(SIRT1)/AMP-activated protein kinase-α/NF-κB pathway to reduce the production of inflammatory factors mediated OGD/R in hippocampal neurons [18]. Moreover, miR-186-5p, a member of the miRNA family, could also regulate inflammatory processes. Specifically, miR-186-5p refrained glial cells activation in spinal nerve ligation (SNL) via targeting chemokine ligand 13 (CXCL13) / C-X-C motif chemokine receptor type 5(CXCR5) axis in a neuropathic pain model, thereby reducing the release of inflammatory factors and neuropathic pain [19]. In addition, Li et al. found that miR-186-5p advanced the atherosclerotic lipids accumulation expansion and aggrandized the pro-inflammatory cytokines secretion in macrophages, which eventually led to the acute coronary syndrome (ACS) onset [20]. However, the mechanism of miR-186-5p in the inflammatory response aroused by ischemia-reperfusion injury remains unknown.

C1q/tumor necrosis factor-related protein 3 (CTRP3) is one of the CTRP family members, which mediates inflammatory processes [21]. For instance, CTRP3 plays a role in anti-atherosclerosis by effectively suppressing the inflammatory response and endothelial dysfunction induced by oxidized low-density lipoprotein (ox-LDL) in aortic endothelial cells of rats [22]. What’s more, in diabetic retinopathy (DR), CTRP3 overexpression improved the responsiveness of ARPE-19 cells to stimulation of high glucose (HG). CTRP3 overexpression also reduced the oxidative stress induced by HG in ARPE-19 cells, lowered reactive oxygen species (ROS) levels and malondialdehyde (MDA), and raised superoxide dismutase (SOD) activity [23]. Those data revealed that CTRP3 is a powerful anti-inflammatory and anti-oxidative stress mediator.

Our previous study found that OIP5-AS1 and CTRP3 were both lowly-expressed in the cerebral lesions of MCAO/R rats, while miR-186-5 was upregulated. Hence, we intended to investigate the lncRNA OIP5-AS1/miR-186-5p/CTRP3 axis in MCAO/R induced neurological deficits and neuroinflammation.

Section snippets

Clinical specimen collection and processing

The blood was collected from patients with acute stroke (onset within 24 h) in The People's Hospital of Linyi, Shandong from June 2018 to June 2019. A total of 30 clinical samples were obtained from 15 I/R patients and 15 healthy controls. Cells in the blood samples were removed through low-speed centrifugation, and the plasma was collected and stored at −80 ℃ in a freezer. This study met with the approval of the medical ethics committee of the People's Hospital of Linyi, Shandong. All patients

Expression characteristics of OIP5-AS1 and miR-186-5p in cerebral ischemia

In order to certify the expressions of OIP5-AS1 and miR-186-5p in cerebral ischemic stroke, we detected their expressions in acute stroke patients (IR), tMCAO/R model rats and OGD/R model cells using qRT-PCR. The results manifested that compared with the healthy population, OIP5-AS1 was significantly down-regulated in IR (P < 0.05, Fig. 1A), while miR-186-5p was increased in IR (P < 0.05, Fig. 1B). Likewise, OIP5-AS1 expression was also downregulated in tMCAO/R rats and OGD/R treated BV2 cells,

Discussion

In this paper, we found that OIP5-AS1 and CTRP3 were low-expressed both in the in vivo and in vitro hypoxia-ischemia model, while miR-186-5p was highly expressed. OIP5-AS1 overexpression attenuated microglia/macrophage activation, inflammatory response and oxidative stress induced by hypoxia-ischemia, and diminished infarct volume and neuronal apoptosis. Hence, OIP5-AS1 protected rat against MCAO/R mediated neurological deficits.

It is now acknowledged that a variety of lncRNAs participate in

Ethics statement

Our study was approved by the Ethics Review Board of The People's Hospital of Linyi.

Data availability statement

The data sets used and analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not- for- profit sectors.

CRediT authorship contribution statement

Yuqin Chen: Writing - original draft, Writing - review & editing. Weihua Liu: Data curation, Investigation. Qingyun Sun: Supervision, Software. Hongyu Chen: Visualization, Validation. Yufen Li: Conceptualization, Methodology.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Citation Excerpt :
NP symptoms in SCI rats can be mitigated when upregulated lncRNAs are suppressed, suggesting that lncRNAs are indispensable to NP development. Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) is one lncRNA and abates neuronal injury by alleviating inflammation and oxidative stress in the brain of middle cerebral artery occlusion/reperfusion (MCAO/R) rats [22]. In addition to lncRNAs, microRNAs (miRNAs), another group of small non-coding RNAs, show abnormal profiles in SCI and play a critical role in the disease [23–25].
Both Tetramethylpyrazine (TMPZ) and Astragaloside IV (AGS-IV) can ameliorate neuronal apoptosis and neuroinflammation in CNS diseases. This study revolves around the underlying mechanism of TMPZ and AGS-IV in spinal cord injury (SCI)-associated neuropathic pain (NP).
An in-vivo NP model was constructed in Sprague-Dawley (SD) rats via SCI. qRT-PCR was employed to detect OIP5-AS1 and miR-34a. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of the rats were evaluated. Neuronal apoptosis in the spinal cord of rats was examined by Nissl staining and TUNEL staining. The interactions between OIP5-AS1 and miR-34a as well as miR-34a and Sirt1 were investigated through dual luciferase assay and RIP assay. The protein expressions of Bad, Bax, Caspase-3, iNOS, COX2, NF-κB, and Sirt1 were examined by western blot.
TMPZ and AGS-IV combination relieved behavioral symptoms of neuropathic pain in the SCI rat model, enhanced the levels of OIP5-AS1 and Sirt1, and lowered the profile of miR-34a. OIP5-AS1 downregulation weakened the neuroprotective function of TMPZ and AGS-IV in SCI rats and reversed their anti-inflammatory and anti-apoptotic effects on LPS-elicited primary spinal cord neurons. miR-34a was identified as a target of OIP5-AS1. Upregulated miR-34a partly abated the protective functions of TMPZ and AGS-IV in primary spinal cord neurons. Additionally, miR-34a targeted and repressed Sirt1, thus activating the NF-κB pathway and inflammatory reactions. Sirt1 inhibition reduced the protective effects mediated by OIP5-AS1.
TMPZ and AGS-IV ameliorate SCI-elicited NP via the OIP5-AS1/miR-34a/Sirt1/NF-κB pathway.

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Up-regulating lncRNA OIP5-AS1 protects neuron injury against cerebral hypoxia-ischemia induced inflammation and oxidative stress in microglia/macrophage through activating CTRP3 via sponging miR-186-5p

Highlights

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Clinical specimen collection and processing

Expression characteristics of OIP5-AS1 and miR-186-5p in cerebral ischemia

Discussion

Ethics statement

Data availability statement

Funding

CRediT authorship contribution statement

Declaration of Competing Interest

Biomed. Pharmacother.

Biochem. Biophys. Res. Commun.

World Neurosurg.

Diabetes Metab. Syndr.

J. Neuroinflammation.

Eur. J. Cell Biol.

Front. Mol. Neurosci.

Brain Res.

Redox Biol.

Zafirlukast protects blood-brain barrier integrity from ischemic brain injury

Chem. Biol. Interact.

Astaxanthin ameliorates ischemic-hypoxic-induced neurotrophin receptor p75 upregulation in the endothelial cells of neonatal mouse brains

Int. J. Mol. Sci.

Rosmarinic acid protects against experimental diabetes with cerebral ischemia: relation to inflammation response

J. Neuroinflammation.

lncRNA NR_120420 promotes SH-SY5Y cells apoptosis by regulating NF-κB after oxygen and glucose deprivation

Gene.

Long noncoding RNA TUG1 contributes to cerebral ischaemia/reperfusion injury by sponging mir-145 to up-regulate AQP4 expression

J. Cell Mol. Med.

Influence of lncRNA ANRIL on neuronal apoptosis in rats with cerebral infarction by regulating the NF-κB signaling pathway

Eur. Rev. Med. Pharmacol. Sci.

The long noncoding RNA OIP5-AS1 is involved in the regulation of cell proliferation

Anticancer Res.

Long noncoding RNA OIP5-AS1 accelerates the ox-LDL mediated vascular endothelial cells apoptosis through targeting GSK-3β via recruiting EZH2

Am. J. Transl. Res.