Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China; Department of Gynecology, Dalian Women and Children's Medical Group, Dalian, Liaoning, China.
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China; Department of Obstetrics, Dalian Women and Children's Medical Group, Dalian, Liaoning, China.
Tissue Cell. 2021 Dec;73:101660. doi: 10.1016/j.tice.2021.101660. Epub 2021 Oct 2.
Pelvic organ prolapse (POP) is a common disorder in women, and it is characterized by weakening of pelvic supportive structure with extracellular matrix (ECM) degradation. Activating transcription factor 3 (ATF3) was upregulated in anterior vaginal wall tissues of POP patients. We hypothesized that upregulation of ATF3 might contribute to POP development. This study aims to unveil the role of ATF3 in the pathogenesis of POP using a HO-induced in vitro model. Vaginal fibroblasts were isolated from woman with POP-Q stage greater than II and asymptomatic women with normal pelvic floor support. Knockdown of ATF3 enhanced cell viability and decreased cell apoptosis. Flow cytometry and immunnofluorescence showed that ATF3 deficiency inhibited HO-induced ROS production and the expression of 8 OHdG and 4-HNE. Western blot and Real-time PCR analysis revealed that ATF3 deficiency attenuated ECM component degradation (increasing collagen I, collagen III and elastin) and MMPs/TIMPs imbalance (decreasing MMP2 and MMP9 and increasing TIMP2). Moreover, knockdown of ATF3 induced the activation of p38/Nrf2/HO-1 signaling pathway. Further treatment with p38 inhibitor SB203580 abolished the protection of ATF3 deficiency against HO-induced cell damage, which was reverted by Nrf2 activator TBHQ. Thus, ATF3 likely contributes to POP progression by inducing cell apoptosis, oxidative stress and ECM degradation via regulating p38/Nrf2 pathway, which provides a potential therapeutic target for POP.
盆腔器官脱垂（POP）是女性常见的疾病，其特征是盆底支持结构薄弱伴细胞外基质（ECM）降解。在 POP 患者的阴道前壁组织中，激活转录因子 3（ATF3）上调。我们假设 ATF3 的上调可能导致 POP 的发展。本研究旨在通过 HO 诱导的体外模型揭示 ATF3 在 POP 发病机制中的作用。从 POP-Q 分期大于 II 期的 POP 患者和无症状的盆底支撑正常的女性中分离阴道成纤维细胞。ATF3 敲低可增强细胞活力并减少细胞凋亡。流式细胞术和免疫荧光显示，ATF3 缺乏抑制 HO 诱导的 ROS 产生以及 8-羟基脱氧鸟苷（8-OHdG）和 4-羟基壬烯醛（4-HNE）的表达。Western blot 和实时 PCR 分析显示，ATF3 缺乏可减弱 ECM 成分降解（增加胶原 I、胶原 III 和弹性蛋白）和 MMPs/TIMPs 失衡（减少 MMP2 和 MMP9 并增加 TIMP2）。此外，ATF3 敲低可诱导 p38/Nrf2/HO-1 信号通路的激活。进一步用 p38 抑制剂 SB203580 处理可消除 ATF3 缺乏对 HO 诱导的细胞损伤的保护作用，而 Nrf2 激活剂 TBHQ 可逆转该作用。因此，ATF3 通过调节 p38/Nrf2 通路诱导细胞凋亡、氧化应激和 ECM 降解，可能导致 POP 的进展，为 POP 的治疗提供了潜在的靶点。
