TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis.
TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis.
复制标题
TIGAR 通过清除活性氧和抑制细胞凋亡，促进脑预处理诱导的缺血耐受
DOI：
10.1038/srep27096
复制
发表时间：
2016-06-03
影响因子：
4.6
通讯作者：
Sheng R
中科院分区：
文献类型：
--
作者：
Zhou JH;Zhang TT;Song DD;Xia YF;Qin ZH;Sheng R
以往的研究表明TIGAR（TP 53-induced glycolysis and apoptosis regulator，TP 53）通过增强磷酸戊糖途径（pentose phosphate pathway，PPP）的流量和保护线粒体功能，对缺血性脑损伤具有保护作用。本研究旨在探讨TIGAR在脑预适应中的作用。在原代培养的皮层神经元和小鼠上建立了缺血预处理（IPC）和异氟醚预处理（ISO）模型。IPC和ISO均增加皮层神经元中TIGAR的表达。预处理可能通过SP1转录因子上调TIGAR。慢病毒介导的TIGAR基因敲减可显著抑制IPC和ISO诱导的缺血耐受。ISO还增加了小鼠皮层和海马的TIGAR，减轻了随后的脑缺血再灌注损伤，而ISO诱导的缺血耐受则随着小鼠脑中TIGAR的敲低而消除。ISO增加NADPH和谷胱甘肽（GSH）的产生，并清除活性氧（ROS），而TIGAR敲低降低GSH和NADPH的产生，并增加ROS的水平。ROS清除剂NAC和PPP产物NADPH的补充有效地挽救了由TIGAR缺陷引起的神经元损伤。值得注意的是，TIGAR敲低抑制皮质神经元中ISO诱导的抗凋亡作用。这些结果表明，TIGAR通过减少ROS和随后的细胞凋亡参与脑预适应。
Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis.