QSOX1 regulates trophoblastic apoptosis in preeclampsia through hydrogen peroxide production

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.

Keywords:

• Apoptosis
• trophoblast
• hydrogen peroxide
• preeclampsia
• QSOX1

Acknowledgements

This study was supported by the “111 program” of Ministry of Education PRC and State Administration of Foreign Experts Affairs PRC., and State International Collaborative Laboratory of Reproduction and Development.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by grants from the National Natural Sciences Foundation of China (81520108013 to H.Q; 81671488 to C.T, 81701479 to F.Z, 81701480 to S.G), Ministry of Science and Technology of China (2016YFC1000407 to H.Q), Chongqing Municipal Education Commission (CXTDX201601014 to H.Q), Commission of Science and Technology of Chongqing Municipality (cstc2017jcyjBX0045 to C.T).