QSOX1 regulates trophoblastic apoptosis in preeclampsia through hydrogen peroxide production

Jinjin Li,Chao Tong,Ping Xu,Lianlian Wang,Ting-Li Han,Li Wen,Xiaofang Luo,Bin Tan,Fangyu Zhu,Shunping Gui,Rufei Gao,Hongbo Qi,Philip N Baker

doi:10.1080/14767058.2018.1471459

Abstract

Objective: Oxidative stress plays a significant role in the pathogenesis of preeclampsia (PE), by inducing trophoblast cell death and consequent placental dysfunction. Quiescin sulfhydryl oxidase 1 (QSOX1) is upregulated in many types of cancer cells; it promotes disulfide bond formation as well as hydrogen peroxide (H2O2) production. The aims of present study are to investigate the expression pattern of QSOX1 in placentae of pregnancies complicated by PE and the role of QSOX1 in the regulation of trophoblastic function, thus providing in-depth understanding of the putative involvement of QSOX1 in the development of PE.Methods: Human term placenta from normal pregnancies and from pregnancies complicated by PE was collected to measure QSOX1 expression and H2O2 levels. Down-regulation of QSOX1 in HTR-8/SVneo cells was achieved by siRNA interference. An in vitro cellular PE model was generated by hypoxic incubation. Protein expression levels were assessed by Western blotting, and H2O2 levels were determined in the cell culture medium as well as in the cell lysate. Trophoblast apoptosis was evaluated by TUNEL staining.Results: QSOX1 was overexpressed in the PE placenta. Inhibition of QSOX1 expression in HTR-8/SVneo cells attenuated cell apoptosis and intracellular H2O2 levels. Hypoxia-induced QSOX1 expression in HTR-8/SVneo cells and led to apoptosis of HTR-8/SVneo cells, and knock-down of QSOX1 rescued hypoxia-induced trophoblast apoptosis.Conclusions: Hypoxia-induced upregulation of QSOX1 and a consequent elevation in intracellular H2O2 increased apoptosis in placentae of pregnancies complicated by PE.

Highlights

Preeclampsia (PE) is a pregnancy-specific disorder and one of the main causes of maternal and perinatal mortality [1]
PE placentae were associated with elevated Quiescin sulfhydryl oxidase 1 (QSOX1) expression and H2O2 production QSOX1 mRNA levels in normal and PE placentae were determined by qRT-PCR; QSOX1 mRNA was elevated by 30.7% in the PE group compare to the normal group (p
QSOX1 regulated H2O2 production in HTR8/SVneo trophoblast cells To investigate the regulatory effect of QSOX1 on H2O2 generation by trophoblast cells, QSOX1 deficient trophoblast cells were established by siRNA interference

Summary

Introduction

Preeclampsia (PE) is a pregnancy-specific disorder and one of the main causes of maternal and perinatal mortality [1]. It is diagnosed by newly increased blood pressure and proteinuria after 20 weeks of gestation [1,2]. Quiescin sulfhydryl oxidase 1 (QSOX1) is a member of the QSOX family that belongs to a class of flavin adenine dinucleotide (FAD)-dependent thiol oxidases. It promotes the formation of disulfide bonds in peptide and protein, and reduces molecular oxygen(O2) to hydrogen peroxide(H2O2) through the reaction: 2R-SH+O2→R-S-SR+H2O2 [12]. The role of QSOX1 in the regulation of H2O2 production in trophoblast cells remains to be addressed

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Results

Conclusion