Abstract
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 H(2)O(2) 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.
Highlights
Granulosa cell (GC) apoptosis is the main cause of follicular atresia, and oxidative stress is involved in this process
As expected from the mouse follicular granulosa cells (MGCs), our Quantitative RT-PCR (qRT-PCR) data shown in Fig. 7D confirmed that H2O2 treatment failed to induce mRNA levels of apoptosis-related genes, Bim, TRAIL, FasL, and caspase-3, when the MGCs were treated with insulin
When using 3-nitropropionic acid (3-NP) to inject mice or H2O2 to treat primary cultured MGCs, it was found that FoxO1 expression was dramatically up-regulated in the oxidative stress condition, followed by elevation of the apoptosis-related gene expressions as well as an increase of cell apoptosis in MGCs (Figs. 1– 4)
Summary
Granulosa cell (GC) apoptosis is the main cause of follicular atresia, and oxidative stress is involved in this process. The involvement of FoxO1 in oxidative stress-induced apoptosis of mouse follicular granulosa cells (MGCs) was investigated in vivo and in vitro. FoxO1 triggers the expression of apoptosis-related genes, including Bim, FasL, Puma, and TRAIL, in response to oxidative stress and induces neuronal death in neurodegenerative diseases [52]. We employed oxidative models to show that oxidant-induced FoxO1 plays a primary role in regulating mouse follicular granulosa cell (MGC) apoptosis. Our results suggest that the oxidative stress in MGCs initiates cell apoptosis by up-regulating the FoxO1 expression and increasing FoxO1 nuclear localization, promoting apoptosis-related gene expression Such a mechanism of MGC apoptosis eventually may lead to follicular atresia in mice
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