EZH2在卵巢颗粒细胞氧化应激反应诱导子宫内膜异位症相关不孕中的作用  

Role of EZH2 in endometriosis-related infertility induced by oxidative stress in ovarian granulosa cells

作　　者：余晓燕[1] 王烈宏[1] 杨惠林[1] 马英兰[1] 李燕子[1] YU Xiao-yan;WANG Lie-hong;YANG Hui-lin;MA Ying-lan;LI Yan-zi(Department of Reproductive Center,Qinghai Red Cross Hospital,Xining,Qinghai 810000,China)

机构地区：[1]青海红十字医院生殖中心,青海西宁810000

出　　处：《中华全科医学》2022年第11期1836-1840,1877,共6页Chinese Journal of General Practice

基　　金：青海省自然科学基金项目(2019-q-051)。

摘　　要：目的探讨Zeste基因增强子同源物2(EZH2)在卵巢颗粒细胞(GCs)氧化应激反应(OS)诱导的子宫内膜异位症(EM)相关不孕中的作用。方法收集2019年4月—2020年11月青海红十字医院生殖医学科66例深浸润性EM患者和63例输卵管不孕症患者(对照组)的GCs。采用流式细胞术分析GCs中活性氧(ROS)水平。建立EZH2低表达COV434细胞模型,采用H_(2)O_(2)处理,通过SA-β-gal测定细胞衰老情况。建立小鼠EM模型,通过腹腔注射EZH2抑制剂DZNep进行治疗,并进行为期6个月的生育力测试。结果与对照组比较,EM组患者慢性盆腔疼痛评分、痛经疼痛评分和血清CA-125抗原均显著增加(均P<0.001),并且平均取卵数量、平均成熟卵母细胞数量、平均2 PN胚胎数量、平均优质胚胎数量以及每个胚胎移植周期的临床妊娠率均显著降低(均P<0.001)。与对照GCs相比,EM患者GCs中的细胞内ROS显著增加(3.62±0.26 vs.12.25±0.74,P<0.001),并且GCs中诱导型一氧化氮合酶(iNOS)和超氧化物歧化酶1(SOD1)蛋白表达显著减少(均P<0.05)。EZH2敲低显著逆转了H_(2)O_(2)诱导的ROS水平、SA-β-Gal活性增加(均P<0.05),并下调衰老相关蛋白表达(均P<0.05)。EM+DZNep组中的子宫内膜异位病变尺寸比EM组显著减小[(433±74)mm^(3)vs.(1624±182)mm^(3),P<0.001],并且每次分娩的平均幼崽数明显大于EM组(均P<0.05)。结论EZH2参与GCs细胞OS诱导的EM相关不孕。Objective To explore the role of enhancer of Zeste homologue 2(EZH2)in ovarian granulosa cells(GCs)and oxidative stress(OS)-induced infertility related to endometriosis(EM).Methods The GCs were collected from 66 patients with deep invasive EM and 63 patients with tubal infertility(control group)in the Department of Reproductive Medicine,Qinghai Red Cross Hospital from April 2019 to November 2020.Flow cytometry was used in analysing the level of ROS in GCs.The COV434 cell model with low EZH2 expression was established in vitro and treated with H_(2)O_(2).Cell senescence was measured by SA-β-gal.A mouse EM model was established,treated with an intraperitoneal injection of the EZH2 inhibitor DZNep and subjected to 6-month fertility test.Results Compared with the control group,the chronic pelvic pain score,dysmenorrhea pain score and serum CA-125 antigen significantly increased in the EM group(all P<0.001),and the number of cells,average number of 2 PN embryos,average number of high-quality embryos and clinical pregnancy rate per embryo transfer cycle significantly decreased(all P<0.001).Compared with control GCs,the intracellular ROS in GCs of patients with EM increased significantly(3.62±0.26 vs.12.25±0.74,P<0.001),and the expression levels of iNOS and SOD1 in the GCs decreased significantly(all P<0.05).EZH2 knockdown significantly reversed H_(2)O_(2)-induced increase in ROS levels and SA-β-Gal activity(all P<0.05)and down-regulated the expression of senescence-related proteins(all P<0.05).The EM lesions in the EM+DZNep group was significantly smaller than those in the EM group[(433±74)mm^(3) vs.(1624±182)mm^(3),P<0.001],and the mean number of pups per delivery was significantly greater than in the EM group(all P<0.05).Conclusion EZH2 is involved in EM-related infertility induced by GC cell OS.

关 键 词：Zeste基因增强子同源物2 卵巢颗粒细胞 氧化应激 子宫内膜异位症 

分 类 号：R711.71[医药卫生—妇产科学]