Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China.
Key Laboratory of Gynecology Oncology, Qilu Hospital, Jinan, China.
Neurourol Urodyn. 2024 Jun;43(5):1217-1229. doi: 10.1002/nau.25455. Epub 2024 Apr 1.
The pathogenesis of pelvic organ prolapse (POP), an age-related disease, has not been fully elucidated. Therapeutic targets of POP are limited. Silencing information regulator 2 related enzyme 1 (SIRT1), a gene considered capable of regulating oxidative stress and cellular senescence, has been widely demonstrated involved in aging and age-related diseases. The present study aimed to explore the role of SIRT1 in POP in vivo and in vitro.
Expression levels of SIRT1 in uterosacral ligament (USL) tissues from patients with or without POP were measured using immunohistochemical assays. SRT1720, a SIRT1 agonist, was used to upregulate SIRT1, and hydrogen peroxide (HO) was used to establish an oxidative stress model in human uterosacral ligament fibroblasts (hUSLFs). The effects of SIRT1 on cell viability, apoptosis, senescence, and reactive oxygen species (ROS) levels were detected, respectively. Western blot assays were used to examine expression levels of apoptosis- and senescence-associated biomarkers. Unpaired Student's t test, Mann-Whitney U test, χ test, and one-way ANOVA were performed for determining statistically significant differences.
Compared to the control group, expression levels of SIRT1 were downregulated in USL tissues and hUSLFs from patients with POP, and associated with stage (p < 0.05). hUSLFs of patients with POP had lower growth rates (p < 0.0001) than those of the control group, which were improved by upregulating SIRT1 (p < 0.05). The senescent proportion was higher in the POP group than the control group (43.63 ± 10.62% vs. 4.84 ± 5.32%, p < 0.0001), which could be reduced by upregulating SIRT1 (p < 0.0001). High ROS levels in the POP group were also alleviated by SRT1720. HO exposure increased ROS levels, inhibited proliferation, and triggered apoptosis and senescence in hUSLFs of patients without POP in a concentration-dependent manner. Further, these damages were alleviated by pretreatment with SRT1720.
SIRT1 is downregulated in patients with POP, and the development of SIRT1 activators or agonists may have applications in the treatment and prevention of POP through antioxidative stress and antisenescence effects.
盆腔器官脱垂（POP）是一种与年龄相关的疾病，其发病机制尚未完全阐明。POP 的治疗靶点有限。沉默信息调节因子 2 相关酶 1（SIRT1）是一种被认为能够调节氧化应激和细胞衰老的基因，它广泛参与衰老和与年龄相关的疾病。本研究旨在探讨 SIRT1 在体内和体外 POP 中的作用。
采用免疫组织化学法检测有或无 POP 患者的子宫骶骨韧带（USL）组织中 SIRT1 的表达水平。使用 SIRT1 激动剂 SRT1720 上调 SIRT1，用过氧化氢（HO）建立人子宫骶骨韧带成纤维细胞（hUSLFs）的氧化应激模型。分别检测 SIRT1 对细胞活力、凋亡、衰老和活性氧（ROS）水平的影响。Western blot 检测凋亡和衰老相关生物标志物的表达水平。采用单因素方差分析、Mann-Whitney U 检验、卡方检验和独立样本 t 检验进行统计学分析。
与对照组相比，POP 患者的 USL 组织和 hUSLFs 中 SIRT1 的表达水平下调，且与分期有关（p<0.05）。POP 患者的 hUSLFs 生长速度低于对照组（p<0.0001），上调 SIRT1 后有所改善（p<0.05）。POP 组的衰老比例高于对照组（43.63±10.62% vs. 4.84±5.32%，p<0.0001），上调 SIRT1 后可降低衰老比例（p<0.0001）。SRT1720 还可减轻 POP 组的高 ROS 水平。HO 暴露以浓度依赖性方式抑制无 POP 患者的 hUSLFs 增殖，并触发细胞凋亡和衰老，同时增加 ROS 水平。进一步的，SRT1720 预处理可减轻这些损伤。
SIRT1 在 POP 患者中下调，开发 SIRT1 激活剂或激动剂可能通过抗氧化应激和抗衰老作用在 POP 的治疗和预防中具有应用前景。
