TIGAR alleviates ischemia/reperfusion-induced autophagy and ischemic brain injury
TIGAR alleviates ischemia/reperfusion-induced autophagy and ischemic brain injury
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TIGAR 减轻缺血/再灌注诱导的自噬和缺血性脑损伤
DOI：
10.1016/j.freeradbiomed.2019.04.002
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发表时间：
2019-06-01
影响因子：
7.4
通讯作者：
Qin, Zheng-Hong
中科院分区：
文献类型：
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作者：
Zhang, Ding-Mei;Zhang, Tian;Qin, Zheng-Hong
自噬在脑缺血/再灌注（I/R）引起的神经元损伤中起保护和致病作用。我们以前的研究表明，TP 53诱导的糖酵解和凋亡调节因子（TIGAR）改善I/R诱导的脑损伤，并减少抗癌药物诱导的自噬激活。然而，TIGAR是否在脑I/R损伤中对自噬起调节作用仍不清楚。本研究的目的是研究TIGAR对I/R诱导的自噬激活和缺血性神经元损伤的作用，在体内和体外中风模型中使用TIGAR转基因（tg-TIGAR）小鼠和TIGAR敲除（ko-TIGAR）小鼠。本研究证实了自噬在I/R后被激活。在tg-TIGAR小鼠中TIGAR的过表达显著降低I/R诱导的自噬激活并减轻脑损伤，而在ko-TIGAR小鼠中TIGAR的敲除增强I/R诱导的自噬激活并加重体内和体外脑损伤。在OGD/R后，tg-TIGAR和ko-TIGAR原代神经元中自噬的不同活性在很大程度上被这些神经元中TIGAR的敲低或重新表达所逆转。自噬抑制剂3-甲基腺嘌呤（3-MA）部分地防止了由ko-TIGAR诱导的脑损伤的加重，而自噬诱导剂雷帕霉素部分地消除了tg-TIGAR的神经保护作用。TIGAR基因敲除可降低mTOR和S6 KP 70的磷酸化水平，在体内和体外I/R和OGD/R后，这两种作用分别被3-MA和NADPH阻断。过表达TIGAR可增加OGD/R条件下磷酸化mTOR和S6 KP 70的水平，这种增强作用可被雷帕霉素抑制。总之，我们目前的数据表明，TIGAR通过调节mTOR-S6 KP 70信号通路抑制自噬，部分地保护神经元免受损伤。
Autophagy has been reported to play protective and pathogenetic roles in cerebral ischemia/reperfusion (I/R)-induced neuronal injury. Our previous studies have shown that TP53-induced glycolysis and apoptosis regulator (TIGAR) ameliorates I/R-induced brain injury and reduces anti-cancer drug-induced autophagy activation. However, if TIGAR plays a regulatory role on autophagy in cerebral I/R injury is still unclear. The purpose of the present study is to investigate the role of TIGAR on I/R-induced autophagy activation and ischemic neuronal injury in vivo and in vitro stroke models using TIGAR-transgenic (tg-TIGAR) mice and TIGAR-knockout (ko-TIGAR) mice. The present study confirmed that autophagy was activated after I/R. Overexpression of TIGAR in tg-TIGAR mice significantly reduced I/R-induced autophagy activation and alleviated brain damage, while knockout of TIGAR in ko-TIGAR mice enhanced I/R-induced autophagy activation and exacerbated brain injury in vivo and in vitro. The different activity of autophagy in tg-TIGAR and ko-TIGAR primary neurons after OGD/R were largely reversed by knockdown or re-expression of TIGAR in these neurons. The autophagy inhibitor 3-methyladenine (3-MA) partly prevented exacerbation of brain damage induced by ko-TIGAR, whereas the autophagy inducer rapamycin partially abolished the neuroprotective effect of tg-TIGAR. Knockout of TIGAR reduced the levels of phosphorylated mTOR and S6KP70, which were blocked by 3-MA and NADPH after I/R and OGD/R in vivo and in vitro, respectively. Overexpression of TIGAR increased the levels of phosphorylated mTOR and S6KP70 under OGD/R condition, this enhancement effect was suppressed by rapamycin. In conclusion, our current data suggest that TIGAR protected against neuronal injury partly through inhibiting autophagy by regulating the mTOR-S6KP70 signaling pathway.