Long non-coding RNA AK038897 aggravates cerebral ischemia/reperfusion injury via acting as a ceRNA for miR-26a-5p to target DAPK1
Long non-coding RNA AK038897 aggravates cerebral ischemia/reperfusion injury via acting as a ceRNA for miR-26a-5p to target DAPK1
复制标题
长非编码RNA AK038897通过作为miR-26a-5p的ceRNA靶向DAPK1加重脑缺血/再灌注损伤
DOI：
10.1016/j.expneurol.2019.01.009
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发表时间：
2019-04-01
影响因子：
5.3
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
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作者：
Wei, Rui;Zhang, Lin;Zhang, Wei
新出现的证据表明，长链非编码RNA （lncRNAs）在缺血性卒中中发挥着重要作用，它作为与microRNAs （miRNAs）竞争的内源性RNA （ceRNAs）来调节某些RNA转录物。AK038897是一种lncRNA，据报道，它在大鼠大脑中响应短暂局灶性缺血而上调。我们的目的是研究AK038897在缺血性脑卒中中的可能调控作用。我们检测到大脑中动脉闭塞/再灌注（MCAO/R）后小鼠大脑中AK038897水平升高，miR-26a-5p水平降低，氧气-葡萄糖剥夺和再氧化（OGD/R）后神经- 2a （N2a）神经母细胞瘤细胞中miR-26a-5p水平降低。通过生物信息学，我们在AK038897和死亡相关蛋白激酶1 （DAPK1）的3'-UTR中发现了共同的miR-26a-5p结合位点，DAPK1是缺血性神经元死亡的中枢介质。MiR-26a-5p过表达可减弱OGD/ r诱导的N2a细胞凋亡。荧光素酶报告基因检测结果证实miR-26a-5p直接靶向DAPK1。进一步研究表明，AK038897直接结合miR-26a-5p，并作为miR-26a-5p的ceRNA调节DAPK1。结果表明，AK038897过表达可拮抗，而AK038897敲低可增强miR-26a-5p对DAPK1表达和OGD/ r诱导的N2a细胞凋亡的抑制作用。此外，AK038897基因敲低对MCAO/ r诱导的脑损伤和神经功能缺陷具有保护作用。总之，我们发现AK038897/miR-26a-5p/DAPK1信号级联是控制脑缺血/再灌注损伤的关键机制。这种级联的药物干预可能为缺血性损伤提供新的治疗方法。
Emerging evidence has suggested a significant role of long non-coding RNAs (lncRNAs) in ischemic stroke by acting as competing endogenous RNAs (ceRNAs) for microRNAs (miRNAs) to regulate certain RNA transcripts. AK038897 is an lncRNA that was reported to be upregulated in rat brains in response to transient focal ischemia. We aimed to investigate the possible regulatory role of AK038897 in ischemic stroke. We detected increased AK038897 and decreased miR-26a-5p levels in mouse brains following middle cerebral artery occlusion/reperfusion (MCAO/R) and in neuro-2A (N2a) neuroblastoma cells following oxygen glucose deprivation and reoxygenation (OGD/R). With bioinformatics, we identified shared putative miR-26a-5p binding sites in AK038897 as well as in the 3'-UTR of death-associated protein kinase 1 (DAPK1), which is a central mediator of ischemic neuronal death. MiR-26a-5p overexpression attenuated OGD/R-induced N2a cell apoptosis. The luciferase reporter assay results confirmed that miR-26a-5p directly targets DAPK1. Further studies showed that AK038897 directly binds to miR-26a-5p and functions as a ceRNA for miR-26a-5p to regulate DAPK1. As a result, AK038897 overexpression antagonized while AK038897 knockdown enhanced the inhibitory effects of miR-26a-5p on DAPK1 expression and OGD/R-induced N2a cell apoptosis. Further, AK038897 knockdown protected against MCAO/R-induced brain injury and neurological deficits in vivo. In summary, we identified a AK038897/miR-26a-5p/DAPK1 signaling cascade as a key mechanism controlling cerebral ischemia/reperfusion injury. Pharmaceutical intervention of this cascade may provide novel therapy for ischemic insults.