Menopause-induced uterine epithelium atrophy results from arachidonic acid/prostaglandin E2 axis inhibition-mediated autophagic cell death.
Menopause-induced uterine epithelium atrophy results from arachidonic acid/prostaglandin E2 axis inhibition-mediated autophagic cell death.
复制标题
花生四烯酸/前列腺素 E2 轴抑制介导的自噬细胞死亡导致更年期诱导的子宫上皮萎缩
DOI：
10.1038/srep31408
复制
发表时间：
2016-08-10
影响因子：
4.6
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Zhou S;Zhao L;Yi T;Wei Y;Zhao X
女性更年期的年龄较晚。绝经的特征是继发于卵巢功能丧失和生殖器官萎缩状态的循环雌激素水平显著降低。然而，这一过程的分子机制尚未完全了解。在这项研究中，我们的目的是调查潜在的分子机制，绝经引起的子宫内膜萎缩。我们的数据显示，自噬在卵巢切除大鼠和围绝经期女性的子宫上皮细胞中被激活。内质网（ER）应激甚至发生在自噬诱导之前。综合生物信息学分析显示，ER应激诱导下游花生四烯酸（AA）释放减少，AA/PGE 2轴下调，导致Akt/mTOR信号通路失活。因此，在子宫上皮细胞中招募自噬体并诱导LC 3依赖性自噬。用外源性E2、PGE 2、salubrinal或RNAi介导的关键自噬基因沉默治疗可以有效地对抗雌激素耗竭诱导的自噬。总的来说，自噬是子宫上皮细胞的一个重要调节因子，是绝经后子宫内膜萎缩的原因。
Women experience menopause later in life. Menopause is characterized by dramatically decreased circulating estrogen level secondary to loss of ovarian function and atrophic state of genital organs. However, the molecular mechanisms for this process are not fully understood. In this study, we aimed to investigate the potential molecular mechanisms that underlie menopause-induced uterine endometrial atrophy. Our data showed that autophagy was activated in the uterine epithelial cells of both ovariectomized rats and peri-menopausal females. Endoplasmic reticulum (ER) stress occurred even prior to autophagy induction. Integrated bioinformatics analysis revealed that ER stress induced downstream decreased release of arachidonic acid (AA) and downregulation of AA/prostaglandin E2 (PGE2) axis, which led to Akt/mTOR signaling pathway inactivation. Consequently, autophagosomes were recruited and LC3-dependent autophagy was induced in uterine epithelial cells. Treatment with exogenous E2, PGE2, salubrinal or RNAi-mediated silencing of key autophagy genes could effectively counteract estrogen depletion-induced autophagy. Collectively, autophagy is a critical regulator of the uterine epithelium that accounts for endometrial atrophy after menopause.