p-JAK2/p-STAT3 信号通路在多囊卵巢综合征大鼠卵泡发育中的作用及机制。

Role and mechanism of the p-JAK2/p-STAT3 signaling pathway in follicular development in PCOS rats.

机构信息

Department of Ob &Gyn, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.

出版信息

Gen Comp Endocrinol. 2023 Jan 1;330:114138. doi: 10.1016/j.ygcen.2022.114138. Epub 2022 Oct 3.

DOI:10.1016/j.ygcen.2022.114138

PMID:36202220

Abstract

OBJECTIVE

To identify the association between the phosphorylated Janus kinase 2/phosphorylated signal transducer and activator of transcription (p-JAK2/p-STAT3) signaling pathway and follicular development in polycystic ovary syndrome (PCOS) rats, and explore the underlying mechanism. To evaluate the role of exogenous JAK2 inhibitor AG490 in the model and the associations among luteinizing hormone/choriogonadotropin receptor (LHCGR), follicle-stimulating hormone receptor (FSHR), cytochrome P450 17α (CYP17a), cytochrome P450 19 (CYP19), and PCOS.

RESULTS

Rat models of PCOS was established. PCOS rats were intraperitoneally treated with double-distilled water (ddH2O)/DMSO/AG490. The rate of ovarian morphological recovery in the AG490 group was significantly higher compared with the DMSO group (83.3 % vs 9.1 %, X = 12.68, P < 0.001). Moreover, the short in the time the estrous cycle was resumed in the AG490 group (hazard ratio = 16.32, P < 0.001) compared with the DMSO group. Compared with the controls, p-JAK2, p-STAT3, LHCGR, and CYP17a expression levels were increased whereas that of FSHR and CYP19 were decreased in the ovaries of PCOS rats. However, an opposite trend was observed after treatment with AG490. Software prediction revealed that the p-STAT3 bound to the promoter regions of LHCGR, FSHR, CYP17a, and CYP19 genes. This finding was confirmed by results of correlation analysis (R = 0.834, -0.836, 0.875 and -0.712, respectively, all P < 0.001).

CONCLUSION

This study demonstrated that the p-JAK2/p-STAT3 signaling pathway was involved in follicular development in PCOS rats by upregulating LHCGR and CYP17a expression, and downregulating that of FSHR and CYP19. AG490 treatment exerted beneficial effects. LHCGR, FSHR, CYP17a, and CYP19 are candidate genes associated with follicular development in PCOS rats.

摘要

目的

鉴定磷酸化 Janus 激酶 2/磷酸化信号转导和转录激活因子（p-JAK2/p-STAT3）信号通路与多囊卵巢综合征（PCOS）大鼠卵泡发育之间的关系，并探讨其潜在机制。评估外源性 JAK2 抑制剂 AG490 在模型中的作用以及黄体生成素/促性腺激素受体（LHCGR）、卵泡刺激素受体（FSHR）、细胞色素 P45017α（CYP17a）、细胞色素 P45019（CYP19）与 PCOS 之间的关联。

结果

建立了 PCOS 大鼠模型。PCOS 大鼠经腹腔给予双蒸水（ddH2O）/二甲基亚砜（DMSO）/AG490 处理。与 DMSO 组相比，AG490 组卵巢形态恢复率显著更高（83.3% vs 9.1%，X=12.68，P<0.001）。此外，与 DMSO 组相比，AG490 组恢复动情周期的时间更短（风险比=16.32，P<0.001）。与对照组相比，PCOS 大鼠卵巢中 p-JAK2、p-STAT3、LHCGR 和 CYP17a 的表达水平升高，而 FSHR 和 CYP19 的表达水平降低。然而，在用 AG490 处理后，观察到相反的趋势。软件预测显示 p-STAT3 与 LHCGR、FSHR、CYP17a 和 CYP19 基因的启动子区域结合。相关性分析结果证实了这一发现（R=0.834、-0.836、0.875 和-0.712，均 P<0.001）。