Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia.
Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia.
复制标题
长链非编码 RNA C2dat1 调节 CaMKII delta 表达，通过 NF-kappa B 信号通路促进脑缺血后神经元存活
DOI：
10.1038/cddis.2016.57
复制
发表时间：
2016-03-31
影响因子：
9
通讯作者：
Ji A
中科院分区：
文献类型：
--
作者：
Xu Q;Deng F;Xing Z;Wu Z;Cen B;Xu S;Zhao Z;Nepomuceno R;Bhuiyan MI;Sun D;Wang QJ;Ji A
越来越多的证据表明长链非编码RNA（lncRNA）在多种生物过程中发挥着重要作用。然而，它们在脑缺血中的功能在很大程度上仍然未知。通过对大鼠局灶性脑缺血/再灌注（I/R）模型的lncRNA阵列分析，我们鉴定出CAMK 2D相关转录本1（C2 dat 1）是一种新的I/R诱导的lncRNA，在小鼠局灶性脑缺血模型中调节CaMK Ⅱ δ的表达。小鼠局灶性缺血性脑损伤后C2 dat 1 mRNA表达呈时间依赖性上调，并伴随CaMK Ⅱ δ在转录和蛋白水平表达的增加。C2 dat 1和CAMK 2D的表达模式在小鼠Neuro-2a细胞中被确认为对体外缺血（氧-葡萄糖剥夺/复氧，OGD/R）的响应。敲低C2 dat 1可显著阻断CaMK Ⅱ δ的表达，并增强OGD/R诱导的细胞死亡。从机制上讲，沉默C2 dat 1后CaMK II δ表达的减少抑制了OGD/R诱导的NF-κB信号通路的激活。进一步的分析表明，IKKα和IKKβ表达和磷酸化的下调，以及随后IκBα降解的抑制解释了沉默C2 dat 1引起的NF-κB信号传导活性的抑制。总之，我们发现了一种新的I/R诱导的lncRNA C2 dat 1，其调节CaMKIIδ的表达以影响神经元存活，并且可能是缺血性脑损伤治疗干预的潜在靶点。
Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes. However, their functions in cerebral ischemia remain largely unknown. Through an lncRNA array analysis in a rat model of focal cerebral ischemia/reperfusion (I/R), we have identified CAMK2D-associated transcript 1 (C2dat1) as a novel I/R-induced lncRNA that regulated the expression of CaMKIIδ in murine models of focal cerebral ischemia. C2dat1 mRNA was upregulated in a time-dependent manner in mouse cortical penumbra after focal ischemic brain injury, which was accompanied by increased expression of CaMKIIδ at transcript and protein levels. The expression patterns of C2dat1 and CAMK2D were confirmed in mouse Neuro-2a cells in response to in vitro ischemia (oxygen-glucose deprivation/reoxygenation, OGD/R). Knockdown of C2dat1 resulted in a significant blockade of CaMKIIδ expression, and potentiated OGD/R-induced cell death. Mechanistically, reduced CaMKIIδ expression upon silencing C2dat1 inhibited OGD/R-induced activation of the NF-κB signaling pathway. Further analysis showed that the downregulation of IKKα and IKKβ expression and phosphorylation, and subsequent inhibition of IκBα degradation accounted for the inhibition of the NF-κB signaling activity caused by silencing C2dat1. In summary, we discovered a novel I/R-induced lncRNA C2dat1 that modulates the expression of CaMKIIδ to impact neuronal survival, and may be a potential target for therapeutic intervention of ischemic brain injury.