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
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.
References (41)
- et al.
Long non-coding RNA OIP5-AS1 functions as an oncogene in lung adenocarcinoma through targeting miR-448/Bcl-2
Biomed. Pharmacother.
(2018) - et al.
LncRNA OIP5-AS1 inhibits osteoblast differentiation of valve interstitial cells via miR-137/TWIST11 axis
Biochem. Biophys. Res. Commun.
(2019) - et al.
OIP5-AS1 Attenuates Microangiopathy in Diabetic Mouse by Regulating miR-200b/ACE2
World Neurosurg.
(2020 Jul) - et al.
C1q/TNF-related protein-3 and glucose homeostasis
Diabetes Metab. Syndr.
(2019) - et al.
LncRNA-1810034E14Rik reduces microglia activation in experimental ischemic stroke
J. Neuroinflammation.
(2019) - et al.
LncRNA OIP5-AS1 regulates radioresistance by targeting DYRK1A through miR-369-3p in colorectal cancer cells
Eur. J. Cell Biol.
(2018) - et al.
Long non-coding RNA TUG1 sponges Mir-145a-5p to regulate microglial polarization after oxygen-glucose deprivation
Front. Mol. Neurosci.
(2019) - et al.
C1q/tumor necrosis factor-related protein 3 inhibits oxidative stress during intracerebral hemorrhage via PKA signaling
Brain Res.
(2017) - et al.
Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction
Redox Biol.
(2018) - Lei Liu, M. Locascio Logan, Sylvain Doré, Critical role of Nrf2 in experimental ischemic stroke, Front. Pharmacol....
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.
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2023, International ImmunopharmacologyCitation 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].