Yuan Suzhen, Wen Jingyi, Cheng Jing, Shen Wei, Zhou Su, Yan Wei, Shen Lu, Luo Aiyue, Wang Shixuan
a Department of Obstetrics and Gynecology , Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , Hubei , China.
Cell Cycle. 2016 Nov;15(21):2895-2905. doi: 10.1080/15384101.2016.1208873. Epub 2016 Jul 19.
Follicular atresia is the main process responsible for the loss of follicles and oocytes from the ovary, and it is the root cause of ovarian aging. Apoptosis of granulosa cells (GCs) is the cellular mechanism responsible for follicular atresia in mammals. Recent advances have highlighted fundamental roles for EGR1 in age-related diseases via the induction of apoptosis. In the present study, we found that the expression of EGR1 was significantly increased in aged mouse ovaries compared with young ovaries. Immunohistochemical analysis revealed strongly positive EGR1 staining in atretic follicles, especially in apoptotic granulosa cells. We further showed that EGR1 up-regulation in mouse primary granulosa cells inhibited cell proliferation and promoted apoptosis. In addition, the promotion of apoptosis in GCs by EGR1 increases over time and with reactive oxygen species (ROS) stimulation. Our mechanistic study suggested that EGR1 regulates GC apoptosis in a mitochondria-dependent manner and that this mainly occurs through the NF-κB signaling pathway. In conclusion, our results suggested that age-related up-regulation of EGR1 promotes GC apoptosis in follicle atresia during ovarian aging.
卵泡闭锁是导致卵巢中卵泡和卵母细胞丢失的主要过程，也是卵巢衰老的根本原因。颗粒细胞（GCs）凋亡是哺乳动物卵泡闭锁的细胞机制。最近的研究进展突出了早期生长反应蛋白1（EGR1）通过诱导凋亡在与年龄相关疾病中的重要作用。在本研究中，我们发现与年轻小鼠卵巢相比，老年小鼠卵巢中EGR1的表达显著增加。免疫组织化学分析显示，在闭锁卵泡中，尤其是在凋亡的颗粒细胞中，EGR1染色呈强阳性。我们进一步表明，小鼠原代颗粒细胞中EGR1的上调抑制细胞增殖并促进凋亡。此外，随着时间的推移以及活性氧（ROS）刺激，EGR1对颗粒细胞凋亡的促进作用增强。我们的机制研究表明，EGR1以线粒体依赖的方式调节颗粒细胞凋亡，且这主要通过核因子κB（NF-κB）信号通路发生。总之，我们的结果表明，与年龄相关的EGR1上调在卵巢衰老过程中促进卵泡闭锁时颗粒细胞的凋亡。
