Zeng Xinliu, Yue Zhang, Gao Ying, Jiang Guosong, Zeng Fuqing, Shao Ying, Huang Jiayu, Yin Minuo, Li Yajie
Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Physiol Biochem. 2018;46(3):1078-1090. doi: 10.1159/000488838. Epub 2018 Apr 13.
BACKGROUND/AIMS: Excess fibrosis may lead to chronic pain, scarring, and infertility as endometriosis develops and progresses. The pathogenesis of endometriosis has been linked to transforming growth factor-β (TGF-β), the most potent promoter of fibrosis.
Levels of NR4A1 and P-NR4A1 protein in human endometrial and endometriotic tissue were assessed by western blotting and immunohistochemistry. The expression levels of fibrotic markers in stromal cells were evaluated by real-time PCR. The degree of fibrosis in mouse endometriotic lesions was detected by Masson trichrome and Sirius red staining.
The level of phosphorylated-NR4A1 was higher in ovarian endometriotic tissue than in normal endometrium, and long-term TGF-β1 stimulation phosphorylated NR4A1 in an AKT-dependent manner and then promoted the expression of fibrotic markers. Furthermore, inhibition of NR4A1 in stromal cells increased the TGF-β1-dependent elevated expression of fibrotic markers, and loss of NR4A1 stimulated fibrogenesis in mice with endometriosis. Additionally, Cytosporone B (Csn-B), an NR4A1 agonist, effectively decreased the TGF-β1-dependent elevated expression of fibrotic markers in vitro and significantly inhibited fibrogenesis in vivo.
NR4A1 can regulate fibrosis in endometriosis and may serve as a new target for the treatment of endometriosis.
背景/目的：随着子宫内膜异位症的发展和进展，过度纤维化可能导致慢性疼痛、瘢痕形成和不孕。子宫内膜异位症的发病机制与转化生长因子-β（TGF-β）有关，TGF-β是纤维化最有效的促进因子。
通过蛋白质免疫印迹法和免疫组织化学法评估人子宫内膜和子宫内膜异位组织中NR4A1和磷酸化NR4A1蛋白的水平。通过实时聚合酶链反应评估基质细胞中纤维化标志物的表达水平。通过Masson三色染色法和天狼星红染色法检测小鼠子宫内膜异位病变中的纤维化程度。
卵巢子宫内膜异位组织中磷酸化NR4A1的水平高于正常子宫内膜，长期TGF-β1刺激以AKT依赖的方式使NR4A1磷酸化，进而促进纤维化标志物的表达。此外，抑制基质细胞中的NR4A1会增加TGF-β1依赖的纤维化标志物的高表达，而NR4A1的缺失会刺激子宫内膜异位症小鼠的纤维生成。此外，NR4A1激动剂环孢菌素B（Csn-B）在体外有效降低了TGF-β1依赖的纤维化标志物的高表达，并在体内显著抑制了纤维生成。
NR4A1可调节子宫内膜异位症中的纤维化，可能成为治疗子宫内膜异位症的新靶点。
