期刊
TISSUE & CELL
卷 73, 期 -, 页码 -出版社
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.tice.2021.101660
关键词
Pelvic organ prolapse; Vaginal fibroblasts; Oxidation stress; Extracellular matrix; MMPs/TIMPs; p38/Nrf2 pathway
资金
- 345 Talent Project
- Xingliao Talent Program in Liaoning Province [XLYC1902102]
- Key Research and Development Program of Liaoning Province [201802588]
- Major Special Construction Project of China Medical University [3110118039]
The study reveals that ATF3 plays a crucial role in the progression of pelvic organ prolapse (POP) by inducing cell apoptosis, oxidative stress, and ECM degradation via regulating the p38/Nrf2 pathway. ATF3 may serve as a potential therapeutic target for POP.
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 H2O2-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 H2O2-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 H2O2-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.
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