Blocking lncRNA H19-m R-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury
Blocking lncRNA H19-m R-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury
复制标题
阻断lncRNA H19-m R-19a-Id2轴可减轻缺氧/缺血引起的神经元损伤
DOI：
10.18632/aging.101999
复制
发表时间：
2019-06-15
期刊：
影响因子：
5.2
通讯作者：
Guo, Liemei
中科院分区：
文献类型：
--
作者：
Xiao, Zhipeng;Qiu, Yongming;Guo, Liemei
低氧环境下lncRNA H19 （H19）的表达升高已被认为是多种癌症的有希望的治疗靶点。然而，对H19在缺血性脑卒中中的作用及其机制知之甚少。本研究发现，脑卒中患者血清中H19水平升高，大脑中动脉闭塞/再灌注（MCAO/R）损伤大鼠缺血半暗区及氧糖剥夺（OGD）神经元细胞中H19水平升高。此外，siRNA敲除H19可减轻OGD神经元细胞的细胞凋亡，抑制MCAO/R大鼠的H19可显著降低神经功能缺损、脑梗死体积和神经元凋亡。最后，通过功能的获得和损失研究、双荧光素酶报告实验、RNA免疫沉淀（RIP）和下拉实验，我们证明了miR-19a与H19和Id2 mRNA的3'-UTR的双重竞争相互作用，从而鉴定出H19-miR-19a-Id2轴。通过生物学研究，我们还发现H19-miR-19a-Id2轴调节缺氧诱导的神经元凋亡。本研究表明，鉴定的H19-miR-19a-Id2轴在缺氧诱导的神经元凋亡中起关键作用，阻断该轴可能是缺血性脑损伤的一种新的治疗策略。
Elevated expression of lncRNA H19 (H19) in the setting of hypoxia has been implicated as a promising therapeutic target for various cancers. However, little is known about the impact and underlying mechanism of H19 in ischemic brain stroke. This study found that H19 levels were elevated in the serum of stroke patients, as well as in the ischemic penumbra of rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and neuronal cells with oxygen glucose deprivation (OGD). Further, knockdown of H19 with siRNA alleviated cell apoptosis in OGD neuronal cells, and inhibition of H19 in MCAO/R rats significantly decreased neurological deficit, brain infarct volume and neuronal apoptosis. Lastly, with gain and loss of function studies, dual luciferase reported assay, RNA immunoprecipitation (RIP) and pull-down experiments, we demonstrated the dual competitive interaction of miR-19a with H19 and the 3'-UTR of Id2 mRNA, resulting in the identification of the H19-miR-19a-Id2 axis. With biological studies, we also revealed that H19-miR-19a-Id2 axis modulated hypoxia induced neuronal apoptosis. This study demonstrates that the identified H19-miR-19a-Id2 axis plays a critical role in hypoxia induced neuronal apoptosis, and blocking this axis may serve as a novel therapeutic strategy for ischemic brain injury.