p53 inhibition provides a pivotal protective effect against ischemia-reperfusion injury in vitro via mTOR signaling
p53 inhibition provides a pivotal protective effect against ischemia-reperfusion injury in vitro via mTOR signaling
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DOI：
10.1016/j.brainres.2015.02.009
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发表时间：
2015-04-24
期刊：
影响因子：
2.9
通讯作者：
Xie, Rong
中科院分区：
文献类型：
--
作者：
Li, Xiaomu;Gu, Shixin;Xie, Rong
肿瘤抑制因子p53最近被报道具有许多独立于肿瘤发生的功能，包括缺血期间的神经元存活。哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在调节代谢、细胞生长、发育和细胞存活中起着核心作用。我们最近的工作已经证明了mTOR通路的神经保护作用。考虑到p53也是mTOR的重要调节因子，为了进一步明确p53和mTOR信号通路在神经元缺血再灌注损伤中的作用，我们采用小鼠原代混合培养神经元氧葡萄糖剥夺（OGD）模型体外模拟缺血再灌注损伤。慢病毒系统也被用来抑制或过表达p53，以确定p53的改变是否影响OGD和再灌注损伤。我们的研究结果表明，在OGD和再灌注后的原代混合培养神经元中，p53被激活并抑制mTOR的表达。使用化学抑制剂或慢病毒介导的shRNA抑制p53，通过上调mTOR活性，在原代培养的神经元中表现出抗OGD和再灌注损伤的神经保护作用。这种保护作用可以被雷帕霉素（一种mTOR抑制剂）逆转。相反，p53过表达往往通过下调mTOR活性加剧OGD损伤的有害影响。这些结果表明，p53抑制通过mTOR信号传导对体外缺血再灌注损伤具有关键的保护作用，为脑卒中治疗提供了一个潜在的、有前景的治疗靶点。(C) 2015 Elsevier B.V.保留所有权利。
Tumor suppressor p53 has recently been reported to have numerous functions independent of tumorigenesis, including neuronal survival during ischemia. The mammalian target of rapamycin (mTOR) signaling pathway plays a central role in the regulation of metabolism, cell growth, development, and cell survival. Our recent work has demonstrated the neuroprotective effects of the mTOR pathway. Considering that p53 is also an important regulator of mTOR, to further clarify the role of p53 and the mTOR signaling pathway in neuronal ischemic-reperfusion injury, we used mouse primary mixed cultured neurons with an oxygen glucose deprivation (OGD) model to mimic an ischemic-reperfusion injury in vitro. A lentiviral system was also used to inhibit or overexpress p53 to determine whether p53 alteration affects OGD and reperfusion injury. Our results show that activated p53 was induced and it suppressed mTOR expression in primary mixed cultured neurons after OGD and reperfusion. Inhibiting p53, using either a chemical inhibitor or lentiviral-mediated shRNA, exhibited neuroprotective effects in primary cultured neurons against OGD and reperfusion injury through the upregulation of mTOR activity. Such protective effects could be reversed by rapamycin, an mTOR inhibitor. Conversely, p53 overexpression tended to exacerbate the detrimental effects of OGD injury by downregulating mTOR activity. These results suggest that p53 inhibition has a pivotal protective effect against an in vitro ischemia-reperfusion injury via mTOR signaling and provides a potential and promising therapeutic target for stroke treatment. (C) 2015 Elsevier B.V. All tights reserved.