Inhibition of Long Noncoding RNA SNHG15 Ameliorates Hypoxia/Ischemia-Induced Neuronal Damage by Regulating miR-302a-3p/STAT1/NF-κB Axis

Abstract

Purpose Ischemic brain injury results in high mortality and serious neurologic morbidity. Here, we explored the role of SNHG15 in modulating neuronal damage and microglial inflammation after ischemia stroke. Materials and Methods The hypoxia/ischemia models were induced by middle cerebral artery occlusion in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Quantitative real-time PCR (qRT-PCR) and Western blot were conducted to determine the levels of SNHG15, miR-302a-3p, and STAT1/NF-κB. Moreover, gain- or loss-of functional assays of SNHG15 and miR-302a-3p were conducted. MTT assay was used to evaluate the viability of HT22 cells, and the apoptotic level was determined by flow cytometry. Furthermore, enzyme-linked immunosorbent assay was performed to detect oxidative stress and inflammatory mediators in the ischemia cortex and OGD/R-treated BV2 microglia. Results The SNHG15 and STAT1/NF-κB pathways were both distinctly up-regulated, while miR-302a-3p was notably down-regulated in the ischemia cortex. Additionally, overexpressing SNHG15 dramatically enhanced OGD/R-mediated neuronal apoptosis as well as the expression of oxidative stress and inflammation factors from microglia. In contrast, knocking down SNHG15 or overexpressing miR-302a-3p relieved OGD/R-mediated neuronal apoptosis and microglial activation. Moreover, the rescue experiment testified that overexpressing miR-302a-3p also attenuated SNHG15 up-regulation-induced effects. In terms of the mechanisms, SNHG15 sponged miR-302a-3p and activated STAT1/NF-κB as a competitive endogenous RNA, while miR-302a-3p targeted STAT1 and negatively regulated the STAT1/NF-κB pathway. Conclusion SNHG15 was up-regulated in the hypoxia/ischemia mouse or cell model. The inhibition of SNHG15 ameliorates ischemia/hypoxia-induced neuronal damage and microglial inflammation by regulating the miR-302a-3p/STAT1/NF-κB pathway.

Effect of lncRNA SNHG15 on LPS-induced vascular endothelial cell apoptosis, inflammatory factor expression and oxidative stress by targeting miR-362-3p

“…In addition, SNHG15-silencing significantly attenuated LPS-induced apoptosis and proliferation inhibition of HUVECs. A number of studies have consistently shown that down-regulation of SNHG15 can improve ischemic/hypoxia-induced neuronal injury and microglial inflammation, and inhibit the progression of ischemic stroke (18,19), which is consistent with the protective effect of SNHG15 silencing in this study. These studies suggest that SNHG15 is related to LPS-induced vascular endothelial cell injury, and silencing SNHG15 may be an important strategy based on vascular endothelial cell inhibition of sepsis progression.…”

LncRNA, an Emerging Approach for Neurological Diseases Treatment by Regulating Microglia Polarization

“…SNHG4 can promote M2 polarization in microglia by sponging miR-449c-5p and thereby activating the signal transducer and activator of transcription 6 (STAT6) signaling pathway ( Zhang et al, 2020 ). In contrast, SNHG15 promotes STAT1 and its NF-κB expression by sponging miR-302a-3p, contributing to the M1 polarization of microglia ( Hu et al, 2021 ). In addition, the remaining sponging combinations were lncRNA TUG1/miR-145a-5p promoting M1 polarization, lncRNA HOTAIR/miR-136-5 promoting AKT2 expression and thus upregulating NF-κB for M1 polarization, lncRNA parent expression gene 3 and sponged miR-7a-5p together upregulating nod-like receptor protein 3 (NLRP3) to promote M1 polarization ( Duan et al, 2018 ; Wang et al, 2019 ; Meng et al, 2021 ).…”

“…The role of NF-κB pathway in ischemic stroke has been well described. In a MCAO and in vitro oxygenated glucose deprivation/reoxygenation-induced hypoxia/ischemia, SNHG15 sponges miR-302a-3p thereby promoting STAT1 and NF-κB expression and activating microglia involved in the development of ischemic brain injury ( Hu et al, 2021 ). In ex vivo ischemic stroke experiments, lncRNA-1810034E14Rik may exert anti-inflammatory effects by inhibiting the NF-κB pathway and suppressing microglia activation and p65 hyperphosphorylation, with implications for stroke treatment ( Zhang et al, 2019e ).…”

Emerging Role of LncRNAs in Ischemic Stroke—Novel Insights into the Regulation of Inflammation

“…116 LncRNA SNHG15 increases neuronal damage and microglial inflammation by sponging miR-302a-3p as a competitive endogenous RNA, while this miRNA targets STAT1 and negatively regulates the NF-κB pathway. 88 In addition, Kuai et al 89…”

“… 116 LncRNA SNHG15 increases neuronal damage and microglial inflammation by sponging miR-302a-3p as a competitive endogenous RNA, while this miRNA targets STAT1 and negatively regulates the NF-κB pathway. 88 In addition, Kuai et al 89 and Tian et al 11 revealed that lncRNAs Snhg8 and THRIL regulate inflammation and microglia activation via SIRT1 and neuropilin-1 (NRP1), respectively, by regulating the NF-κB pathway. Thus, lncRNAs might contribute to regulating neuroinflammation and microglia activation by THRIL, NRP1, and STAT1, which further regulate the NF-κB pathway.…”