ATF4 Contributes to Ovulation via Regulating COX2/PGE2 Expression: A Potential Role of ATF4 in PCOS.
ATF4 Contributes to Ovulation via Regulating COX2/PGE2 Expression: A Potential Role of ATF4 in PCOS.
复制标题
ATF4 通过调节 COX2/PGE2 表达促进排卵：ATF4 在 PCOS 中的潜在作用。
DOI：
10.3389/fendo.2018.00669
复制
发表时间：
2018
影响因子：
5.2
通讯作者：
Du Y
中科院分区：
文献类型：
--
作者：
Di F;Liu J;Li S;Yao G;Hong Y;Chen ZJ;Li W;Du Y
排卵障碍常见于高泌乳素血症或多囊卵巢综合征（PCOS）患者。以往的研究表明，ATF 4在细胞凋亡和葡萄糖稳态中起着关键作用，但其在调节生殖功能中的作用尚未得到探讨。本研究探讨了ATF 4在卵巢排卵功能中的作用。采用来自48名新诊断为PCOS的妇女和37名对照的人颗粒细胞（hGCs）来测定ATF 4表达。采用体外培养的hGCs检测ATF 4的上下游基因。将shRNA-Atf 4慢病毒载体（shAtf 4）注射到大鼠卵巢中以建立体内基因敲除模型，以进一步评估来自PCOS妇女的结果的体内相关性。我们发现ATF 4在PCOS患者的hGCs中的表达低于非PCOS妇女的hGCs。在ATF 4敲除后，许多参与卵丘-卵母细胞复合体（COC）扩增、细胞外基质（ECM）重塑和孕酮产生的关键转录物显著下调。ChIP-qPCR分析表明，ATF 4可以直接结合到COX 2启动子，并且ATF 4敲低可以减弱人绒毛膜促性腺激素（hCG）诱导的COX 2表达和PGE 2产生。体内研究表明，shRNA-慢病毒介导的大鼠卵巢Atf 4敲低导致获得的卵母细胞数量减少。总的来说，这些研究结果表明以前未知的作用ATF 4在排卵。此外，PCOS患者中的ATF 4功能障碍可能会影响排卵过程，这可能部分有助于PCOS的发病机制。
Ovulatory disorder is common in patients with hyperprolactinemia or polycystic ovary syndrome (PCOS). Previous studies have shown that ATF4 plays critical role in apoptosis and glucose homeostasis, but its role in regulating reproductive function was not explored. The present study investigated the role of ATF4 in ovarian ovulatory function. Human granulosa cells (hGCs) from 48 women newly diagnosed with PCOS and 37 controls were used to determine ATF4 expression. In vitro cultured hGCs were used to detect the upstream and downstream genes of ATF4. A shRNA- Atf4 lentiviral vector (shAtf4) was injected into rat ovaries to establish an in vivo gene knockdown model to further assess the in vivo relevance of the results from PCOS women. We found that ATF4 expression was lower in hGCs from PCOS patients than in hGCs from non-PCOS women. Many pivotal transcripts involved in cumulus-oocyte complex (COC) expansion, extracellular matrix (ECM) remodeling, and progesterone production were significantly down-regulated after ATF4 knockdown. ChIP-qPCR assays indicated that ATF4 could directly bind to the COX2 promoter and that ATF4 knockdown could attenuate human chorionic gonadotropin (hCG)-induced COX2 expression and PGE2 production. The in vivo study showed that shRNA-lentivirus mediated Atf4 knockdown in rat ovaries led to reduced number of retrieved oocytes. Collectively, these findings suggested previously unknown roles of ATF4 in ovulation. Furthermore, ATF4 malfunction in PCOS patients may impact the ovulation process, which could contribute, in part, to the pathogenesis of PCOS.
登录
查看更多内容
影响因子：
5.8
作者：
Kaur, Surleen;Archer, Kellie J.;Singh, Rita
通讯作者：
Singh, Rita
影响因子：
13.3
作者：
Duffy, Diane M.
通讯作者：
Duffy, Diane M.
影响因子：
6.1
作者：
Fauser, BCJM;Chang, J;Lobo, R
通讯作者：
Lobo, R
影响因子：
6.1
作者：
Duffy, DM;Stouffer, RL
通讯作者：
Stouffer, RL
影响因子：
--
作者：
Fan, Heng-Yu;Liu, Zhilin;Richards, JoAnne S.
通讯作者：
Richards, JoAnne S.