Advanced Oxidation Protein Products Induce G1/G0-Phase Arrest in Ovarian Granulosa Cells via the ROS-JNK/p38 MAPK-p21 Pathway in Premature Ovarian Insufficiency.

Xing-Yu Zhou,Yi-Zhen Yang,Shi-Ling Chen,Jun Zhang,Zhe Wang,Xiao-Min Wu,Xin Li,Xiao-Fei Zhang,Lin-Zi Ma,Ying-Xue Chen,Ke-Ming Zheng,Yu-Dong Liu,Ying Li,Jayeeta Ghose

doi:10.1155/2021/6634718

Abstract

The mechanism underlying the role of oxidative stress and advanced oxidation protein products (AOPPs) in the aetiology of premature ovarian insufficiency (POI) is poorly understood. Here, we investigated the plasma AOPP level in POI patients and the effects of AOPPs on granulosa cells both in vitro and in vivo. KGN cells were treated with different AOPP doses, and cell cycle distribution, intracellular reactive oxygen species (ROS), and protein expression levels were measured. Sprague–Dawley (SD) rats were treated daily with PBS, rat serum albumin, AOPP, or AOPP+ N-acetylcysteine (NAC) for 12 weeks to explore the effect of AOPPs on ovarian function. Plasma AOPP concentrations were significantly higher in both POI and biochemical POI patients than in controls and negatively correlated with anti-Müllerian hormone and the antral follicle count. KGN cells treated with AOPP exhibited G1/G0-phase arrest. AOPP induced G1/G0-phase arrest in KGN cells by activating the ROS-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK)-p21 pathway. Pretreatment with NAC, SP600125, SB203580, and si-p21 blocked AOPP-induced G1/G0-phase arrest. In SD rats, AOPP treatment increased the proportion of atretic follicles, and NAC attenuated the adverse effects of AOPPs in the ovary. In conclusion, we provide mechanistic evidence that AOPPs may induce cell cycle arrest in granulosa cells via the ROS-JNK/p38 MAPK-p21 pathway and thus may be a novel biomarker of POI.

Highlights

Premature ovarian insufficiency (POI) is a disease in which the ovarian reserve is exhausted prematurely before the age of 40 and is characterized by sterility, amenorrhea or oligomenorrhea, hypoestrogenism, and elevated serum folliclestimulating hormone (FSH) concentrations (>25 mIU/ml)
Plasma advanced oxidation protein products (AOPPs) concentrations were significantly higher in both POI and biochemical POI (bPOI) patients than in age- and body mass index- (BMI-)matched controls (Figure 1(a))
Our results indicating that AOPPs accumulate in the plasma of bPOI and POI patients add to the growing evidence that chronic inflammation and oxidative stress may participate in the pathogenesis of POI

Summary

Introduction

Premature ovarian insufficiency (POI) is a disease in which the ovarian reserve is exhausted prematurely before the age of 40 and is characterized by sterility, amenorrhea or oligomenorrhea, hypoestrogenism, and elevated serum folliclestimulating hormone (FSH) concentrations (>25 mIU/ml). Women who suffer from POI for a long period of time are at increased risk for cardiovascular diseases, neurological function impairment, psychological dysfunction, and osteoporosis [1]. Low levels of ROS are essential for biological functions in cells and tissues, such as ovulation and luteolysis in the ovary [2], elevated production of ROS beyond the antioxidant capacity is detrimental to cell function and participates in various human diseases, including diabetes [3], cardiovascular disorders [4], and neurological disorders [5]. Recent studies have reported that POI manifests with elevated serum levels of ROS and oxidative stress markers [6, 7], while excessive oxidative stress can lead to impairment of ovarian function [8]. The mechanism underlying the role of oxidative stress in the aetiology of POI has received limited attention

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