Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility
Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility
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颗粒卵丘细胞过度氧化应激诱导细胞衰老导致子宫内膜异位症相关不孕
DOI：
10.1016/j.redox.2020.101431
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发表时间：
2020-02-01
期刊：
影响因子：
11.4
通讯作者：
Zhang, Songying
中科院分区：
文献类型：
--
作者：
Lin, Xiang;Dai, Yongdong;Zhang, Songying
子宫内膜异位症是女性不孕的重要原因，严重影响患者的身心健康.子宫内膜异位症是一个值得深入研究的公共卫生问题，尤其是子宫内膜异位症相关不孕症的发病机制。本研究旨在阐明卵巢癌相关不孕症的发病机制，其涉及过度氧化应激（OS）诱导的卵巢颗粒细胞（GCs）的病理变化。子宫内膜异位症患者GCs中衰老相关β-半乳糖苷酶（SA β-gal）活性、卵泡液中可溶性糖基化终产物受体（sCRP）表达以及差异表达的衰老相关分泌表型因子（IL-1 β、MMP-9、KGF和FGF碱性蛋白）均是评价获卵数和成熟卵数的有用指标。RNA测序和生物信息学分析表明，子宫内膜异位症GC的衰老表型和加重内质网（ER）应激。靶向ER应激显著减轻OS诱导的GC衰老以及GC中线粒体膜电位（MMP）和三磷酸腺苷（ATP）的降低。此外，褪黑激素管理拯救OS增强ER应力，细胞衰老，MMP和ATP异常的子宫内膜异位症GC在体外和体内。总之，我们的研究结果表明，过量的活性氧通过引起ER应激诱导子宫内膜异位症GC衰老，最终导致子宫内膜异位症相关不孕症，褪黑素可能是子宫内膜异位症相关不孕症的一种新的辅助治疗策略。
Endometriosis an important cause of female infertility and seriously impact physical and psychological health of patients. Endometriosis is now considered to be a public health problem that deserves in-depth investigation, especially the etiopathogenesis of endometriosis-associated infertility. We aimed to illuminate the etiopathogenesis of endometriosis-associated infertility that involve excessive oxidative stress (OS) induced pathological changes of ovary cumulus granulosa cell (GCs). Senescence-associated beta-galactosidase (SA beta-gal) activity in GCs from endometriosis patients, soluble isoform of advanced glycation end products receptor (sRAGE) expression in follicular fluid from endometriosis patients and differentially expressed senescence-associated secretory phenotype factors (IL-1 beta, MMP-9, KGF and FGF basic protein) are all useful indexes to evaluate oocyte retrieval number and mature oocyte number. RNA-sequencing and bioinformatics analysis indicated senescent phenotype of endometriosis GCs and aggravated endoplasmic reticulum (ER) stress in endometriosis GCs. Targeting ER stress significantly alleviated OS-induced GCs senescence as well as mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) reduction in GCs. Moreover, melatonin administration rescued OS-enhanced ER stress, cellular senescence, and MMP and ATP abnormities of endometriosis GCs in vitro and in vivo. In conclusion, our results indicated excessive reactive oxygen species induces senescence of endometriosis GCs via arouse ER stress, which finally contributes to endometriosis-associated infertility, and melatonin may represent a novel adjuvant therapy strategy for endometriosis-associated infertility.