PI3K/Akt and mTOR/p70S6K pathways mediate neuroprotectin D1-induced retinal pigment epithelial cell survival during oxidative stress-induced apoptosis.
PI3K/Akt and mTOR/p70S6K pathways mediate neuroprotectin D1-induced retinal pigment epithelial cell survival during oxidative stress-induced apoptosis.
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DOI：
10.1016/j.exer.2010.03.002
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发表时间：
2010-06
影响因子：
3.4
通讯作者：
Bazan, Nicolas G.
中科院分区：
文献类型：
--
作者：
Faghiri, Zahra;Bazan, Nicolas G.
关键词：
几种形式的视网膜变性的发生和发展涉及过度的、重复的和/或持续的氧化应激，而氧化应激反过来又介导光感受器细胞的损伤和死亡。由于磷脂酰肌醇3-激酶(PI3K)/Akt和mTOR/p70S6-激酶通路是面临氧化应激的细胞生存信号的一部分，我们探讨了二十二碳六烯酸衍生的神经保护素D1(NPD1)是否通过这一通路介导了单次和/或重复氧化应激下的生存。为此，我们使用了人视网膜色素上皮(ARPE-19)细胞，受到过氧化氢(H_2O_2)和肿瘤坏死因子-α(肿瘤坏死因子-α)的刺激。我们发现，在单剂量氧化应激诱导的细胞凋亡中，Akt、mTOR和p70S6K的磷酸化都具有时间和剂量依赖性。Wortmannin和雷帕霉素分别抑制PI3K和mTOR/p70S6K可增加单次氧化应激诱导的细胞凋亡，抑制Akt和p70S6K的磷酸化。两次低剂量、非损伤性氧化可诱导细胞凋亡，并上调Akt、mTOR和p70S6K的表达，而三次低剂量暴露的细胞经较长时间处理后，Akt、mTOR或p70S6K的水平没有发生变化，但与高剂量相比，细胞的凋亡率增加。在Akt、mTOR和p70S6K磷酸化高峰期(即诱导后30分钟)单次或短期重复氧化应激后去除氧化应激诱导剂可导致恢复，16小时后未见细胞凋亡。当氧化应激在最后一次暴露30分钟后被消除时，用三种低剂量应激诱导的细胞没有表现出恢复。NPD1保护RPE细胞免受单次和重复氧化应激诱导的细胞凋亡，并促进更高水平的磷酸化Akt、mTOR和p70S6K。综上所述，我们的结果表明：a)重复的氧化应激是剂量依赖的，不能通过去除氧化应激诱导剂来恢复；b)PI3K/Akt和mTOR/p70S6K通路在对抗氧化应激诱导的ARPE-19细胞凋亡中起主要作用；c)在这些条件下，NPD1通过诱导PI3K/Akt和mTOR/p70S6K通路发挥保护作用。
The initiation and progression of several forms of retinal degenerations involve excessive, repetitive, and/or sustained oxidative stress that, in turn, mediate photoreceptor cell damage and death. Since phosphatidylinositol 3-kinase (PI3K)/Akt and mTOR/p70S6-kinase pathways are part of survival signaling in cells confronted with oxidative stress, we asked whether or not docosahexaenoic acid-derived neuroprotectin D1 (NPD1) mediates survival upon single-dose and/or repetitive oxidative stress through this pathway. For this purpose, we used human retinal pigment epithelial (ARPE-19) cells challenged by exposure to hydrogen peroxide (H2O2) plus tumor necrosis factor alpha (TNF-α). We found that in single-dose oxidative stress-induced apoptosis, phosphorylation of Akt, mTOR, and p70S6K was both time- and dose-dependent. Inhibition of PI3K or mTOR/p70S6K by wortmannin and rapamycin, respectively, increased apoptosis and inhibited phosphorylation of Akt and p70S6K induced by single-dose oxidative stress. While two exposures of a low-dose, non-damaging oxidation induced apoptosis and upregulation of Akt, mTOR, and p70S6K, longer treatment of the cells with three exposures of low dose to low-dose stress showed no changes in the levels of Akt, mTOR, or p70S6K, and resulted in enhanced apoptosis compared to higher doses. Removing the oxidative stress-inducing agents following the single-dose or short term repetitive oxidative stress at the peak of Akt, mTOR, and p70S6K phosphorylation (i.e, 30 minutes after induction) led to recovery, with no apoptosis after 16 hours of incubation. Cells that were induced with three low doses of stress did not show recovery when oxidative stress was removed 30 minutes after the last exposure. NPD1 protected the RPE cells against both single-dose and repetitive oxidative stress-induced apoptosis and promoted higher levels of phosphorylated Akt, mTOR, and p70S6K. Together, our results show that a) repetitive oxidative stress is dose dependent and may not be recovered by removing the oxidative stress-inducing agents, b) PI3K/Akt and mTOR/p70S6K pathways play a major role in the protection against oxidative stress-induced apoptosis in ARPE-19 cells, and c) NPD1 exerts protection under these conditions by inducing PI3K/Akt and mTOR/p70S6K pathways.
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影响因子：
3.4
作者：
Nicolas, MG;Fujiki, K;Kana, A
通讯作者：
Kana, A
DOI：
10.1073/pnas.0705963104
发表时间：
2007-08-07
影响因子：
11.1
作者：
Mukherjee, Pranab K.;Marcheselli, Victor L.;Bazan, Nicolas G.
通讯作者：
Bazan, Nicolas G.
影响因子：
4.8
作者：
Wan, XL;Helman, LJ
通讯作者：
Helman, LJ
影响因子：
15.9
作者：
ISHII, Y;PARTRIDGE, CA;MALIK, AB
通讯作者：
MALIK, AB
影响因子：
4.4
作者：
Yang, Ping;Peairs, James J.;Jaffe, Glenn J.
通讯作者：
Jaffe, Glenn J.