Involvement of the Up-regulated FoxO1 Expression in Follicular Granulosa Cell Apoptosis Induced by Oxidative Stress
Involvement of the Up-regulated FoxO1 Expression in Follicular Granulosa Cell Apoptosis Induced by Oxidative Stress
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DOI：
10.1074/jbc.m112.349902
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发表时间：
2012-07-27
影响因子：
4.8
通讯作者：
Liu, Honglin
中科院分区：
文献类型：
--
作者：
Shen, Ming;Lin, Fei;Liu, Honglin
卵泡闭锁在雌性哺乳动物卵巢中很常见，大多数卵泡在生长和发育的任何阶段都会发生退化。氧化应激会引发颗粒细胞凋亡，这被认为是卵泡闭锁的主要原因。然而，氧化应激诱导卵泡闭锁的潜在机制仍不清楚。 FoxO 转录因子被认为是氧化应激和细胞凋亡调节中的关键介质。在这项研究中，我们在体内和体外研究了 FoxO1 在氧化应激诱导的小鼠滤泡颗粒细胞 (MGC) 凋亡中的作用。结果发现，当小鼠接受氧化剂处理时，细胞凋亡信号的增加与 MGC 中 FoxO1 表达的升高相关。相应地，FoxO1靶基因，如促凋亡基因和抗氧化基因的表达也上调。在原代培养的 MGC 中，H2O2 处理导致 FoxO1 核易位。对 FoxO1 过表达和敲低的进一步研究证明了 FoxO1 在氧化应激诱导 MGC 凋亡中的关键作用。最后，胰岛素处理使 FoxO1 失活证实氧化应激诱导的 FoxO1 在上调 MGC 下游凋亡相关基因的表达中发挥关键作用。我们的结果表明，氧化应激上调 FoxO1 会导致颗粒细胞凋亡，最终导致小鼠卵泡闭锁。
Follicular atresia is common in female mammalian ovaries, where most follicles undergo degeneration at any stage of growth and development. Oxidative stress gives rise to triggering granulosa cell apoptosis, which has been suggested as a major cause of follicular atresia. However, the underlying mechanism by which the oxidative stress induces follicular atresia remains unclear. FoxO transcription factors are known as critical mediators in the regulation of oxidative stress and apoptosis. In this study, the involvement of FoxO1 in oxidative stress-induced apoptosis of mouse follicular granulosa cells (MGCs) was investigated in vivo and in vitro. It was observed that increased apoptotic signals correlated with elevated expression of FoxO1 in MGCs when mice were treated with the oxidant. Correspondingly, the expressions of FoxO1 target genes, such as proapoptotic genes and antioxidative genes, were also up-regulated. In primary cultured MGCs, treatment with H2O2 led to FoxO1 nuclear translocation. Further studies with overexpression and knockdown of FoxO1 demonstrated the critical role of FoxO1 in the induction of MGC apoptosis by oxidative stress. Finally, inactivation of FoxO1 by insulin treatment confirmed that FoxO1 induced by oxidative stress played a pivotal role in up-regulating the expression of downstream apoptosis-related genes in MGCs. Our results suggest that up-regulation of FoxO1 by oxidative stress leads to apoptosis of granulosa cells, which eventually results in follicular atresia in mice.