Abstract
Spinal cord ischemia–reperfusion injury (SCII) is still a serious problem, and the mechanism is not fully elaborated. In the rat SCII model, qRT-PCR was applied to explore the altered expression of miR-9 (miR-9a-5p) after SCII. The biological function of miR-9 and its potential target genes based on bioinformatics analysis and experiment validation in SCII were explored next. Before the surgical procedure of SCII, miR-9 mimic and inhibitor were intrathecally infused. miR-9 mimic improved neurological function. In addition, miR-9 mimic reduced blood-spinal cord barrier (BSCB) disruption, inhibited apoptosis and decreased the expression of IL-6 and IL-1β after SCII. Gene Ontology (GO) analysis demonstrated that the potential target genes of miR-9 were notably enriched in several biological processes, such as “central nervous system development”, “regulation of growth” and “response to cytokine”. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the potential target genes of miR-9 were significantly enriched in several signaling pathways, including “Notch signaling pathway”, “MAPK signaling pathway”, “Focal adhesion” and “Prolactin signaling pathway”. We further found that the protein expression of MAP2K3 and Notch2 were upregulated after SCII while miR-9 mimic reduced the increase of MAP2K3 and Notch2 protein. miR-9 mimic or MAP2K3 inhibitor reduced the release of IL-6 and IL-1β. miR-9 mimic or si-Notch2 reduced the increase of cleaved-caspase3. Moreover, MAP2K3 inhibitor and si-Notch2 reversed the effects of miR-9 inhibitor. In conclusion, overexpression of miR-9 improves neurological outcomes after SCII and might inhibit BSCB disruption, neuroinflammation, and apoptosis through MAP2K3-, or Notch2-mediated signaling pathway in SCII.
Highlights
Spinal cord ischemia reperfusion injury (SCII) is a complication occurring under thoracoabdominal aortic or spinal cord surgery, which brings the risk of paralysis and paraplegia (Li et al, 2015a; Xu & Li, 2020)
It has been discovered that miRNAs might be related to central nervous system (CNS) injury including SCII (Bao et al, 2018; Chi et al, 2014; Huang et al, 2015; Li et al, 2015b; Yao, Wang & Zhang, 2018). miR-27a mimics reduced blood-spinal cord barrier (BSCB) damage induced by neuroinflammation following SCII via inhibiting the NF-κB/IL-1β pathway and negatively regulating the TICAM-2 of the TLR4 signaling pathway (Li et al, 2015b)
MiR-9 mimic improved neurological function following SCII At 48 h after SCII, we assessed the levels of miR-9 by qRT-PCR after intrathecal injection of miR-9 mimic for 3 days. miR-9 mimic significantly increased the expression of miR-9 (p < 0.05) (Fig. 1B)
Summary
Spinal cord ischemia reperfusion injury (SCII) is a complication occurring under thoracoabdominal aortic or spinal cord surgery, which brings the risk of paralysis and paraplegia (Li et al, 2015a; Xu & Li, 2020). Identification of the biological function of miR-9 in spinal cord ischemia-reperfusion injury in rats. It has been discovered that miRNAs might be related to central nervous system (CNS) injury including SCII (Bao et al, 2018; Chi et al, 2014; Huang et al, 2015; Li et al, 2015b; Yao, Wang & Zhang, 2018). MiR-27a mimics reduced blood-spinal cord barrier (BSCB) damage induced by neuroinflammation following SCII via inhibiting the NF-κB/IL-1β pathway and negatively regulating the TICAM-2 of the TLR4 signaling pathway (Li et al, 2015b). In rat models of SCII, miR125b mimic was found to protect against SCII via reducing aberrant p53 network activation-induced apoptosis and neuroinflammation through the downregulation of TP53INP1 (Li et al, 2018c). Several studies have demonstrated altered miRNA expression profiles in spinal cord tissues of SCII models, which implicated the important roles of miRNAs in the pathophysiological mechanism of SCII (Hu, Lv & Yin, 2013; Li et al, 2016a; Liu et al, 2020)
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