Huang Rui, Li Weishuai, Han Dong, Gao Yan, Zheng Dongming, Bi Guorong
Department of Neurology, Shengjing Hospital of China Medical University, 110004, Shenyang, P.R. China.
Cell Death Discov. 2022 May 4;8(1):247. doi: 10.1038/s41420-022-01016-2.
Circular RNAs (circRNAs) have been noted to express in the brain and thus participate in various diseases related to the central nervous system. However, the potential role of circRNAs in cerebral ischemia (CI)-induced vertigo remains unknown. We initially predicted through bioinformatics analysis the poor expression of circ_0000811 related to CI. A mouse model of CI-induced vertigo was then established, which was validated by measurement of escape latency and medial vestibular nucleus (MVN) blood flow, with NeuN/Annexin counterstaining utilized to detect cell apoptosis in the MVN. An oxygen glucose deprivation (OGD)-exposed neuron-like cell model was further established for in vitro gain- and loss- of function assays, with flow cytometry performed to detect cell apoptosis. The poorly expressed circ_0000811, up-regulated miR-15b expression, and down-regulated Prkar2a expression were observed in both mice with CI-induced vertigo and OGD-exposed cells. Our data then demonstrated that circ_0000811 restoration alleviated CI-induced vertigo in mouse models, and that circ_0000811 acted as a miR-15b sponge to inhibit miR-15b expression. Prkar2a was validated as the target gene of miR-15b. Prkar2a restoration was subsequently revealed to repress OGD-induced neuronal apoptosis through JAK2/STAT1 signaling pathway inactivation. Furthermore, inactivation of the JAK2/STAT1 signaling pathway exerted an anti-apoptotic effect in OGD-induced neurons and an alleviatory effect in mice with CI-induced vertigo with Prkar2a overexpression and circ_0000811 overexpression. Taken together, our work suggests that circ_0000811 is involved in neuronal apoptosis of CI-induced vertigo and may be used as a biomarker for ameliorating CI-induced vertigo.
环状RNA（circRNAs）已被发现可在大脑中表达，从而参与各种与中枢神经系统相关的疾病。然而，circRNAs在脑缺血（CI）诱导的眩晕中的潜在作用仍不清楚。我们最初通过生物信息学分析预测了与CI相关的circ_0000811表达水平较低。随后建立了CI诱导眩晕的小鼠模型，通过测量逃避潜伏期和内侧前庭核（MVN）血流进行验证，并利用NeuN/膜联蛋白复染检测MVN中的细胞凋亡。进一步建立了氧糖剥夺（OGD）处理的神经元样细胞模型用于体外功能获得和缺失实验，并通过流式细胞术检测细胞凋亡。在CI诱导眩晕的小鼠和OGD处理的细胞中均观察到circ_0000811表达水平较低、miR-15b表达上调以及Prkar2a表达下调。我们的数据随后表明，circ_0000811的恢复可减轻小鼠模型中CI诱导的眩晕，并且circ_0000811作为miR-15b的海绵来抑制miR-15b的表达。Prkar2a被验证为miR-15b的靶基因。随后发现Prkar2a的恢复可通过JAK2/STAT1信号通路失活来抑制OGD诱导的神经元凋亡。此外，JAK2/STAT1信号通路的失活在OGD诱导的神经元中发挥抗凋亡作用，并在Prkar2a过表达和circ_0000811过表达的CI诱导眩晕小鼠中发挥缓解作用。综上所述，我们的研究表明circ_0000811参与CI诱导眩晕的神经元凋亡，并且可能用作改善CI诱导眩晕的生物标志物。
