Abnormal CYP11A1 gene expression induces excessive autophagy, contributing to the pathogenesis of preeclampsia
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Tianying Pan1,3,*, Guolin He1,3,*, Meng Chen1,3, Chenyi Bao1,3, Yan Chen2,3, Guangyu Liu1,3, Mi Zhou1,3, Shuying Li1,3, Wenming Xu2,3 and Xinghui Liu2,3
1Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
2Joint Laboratory of Reproductive Medicine, Sichuan University-The Chinese University of Hong Kong, Chengdu 610041, China
3Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
*These authors contributed equally to this work
Wenming Xu, email: email@example.com
Xinghui Liu, email: firstname.lastname@example.org
Keywords: CYP11A1, autophagy, preeclampsia, testosterone, androgen receptor
Received: June 12, 2017 Accepted: September 08, 2017 Published: September 22, 2017
Objective: In this study, we investigated the exact mechanism by which excessive CYP11A1 expression impairs the placentation process and whether this causes preeclampsia (PE) in an in vivo model.
Setting and Design: In order to study CYP11A1 overexpression, BeWo cells were transfected with CYP11A1. Pregnenolone, progesterone, and testosterone levels were measured by enzyme linked immunosorbent assays, and levels of autophagy markers were quantified by western blotting and immunofluorescence. Trophoblastic cell invasion was assessed using transwell assays; BeWo cells were treated with testosterone and an androgen receptor (AR) inhibitor (flutamide) to elucidate the invasion mechanism. An adenovirus overexpression rat model was established to investigate CYP11A1 overexpression in vivo and the phenotype was examined. Furthermore, human placenta samples (n = 24) were used to determine whether PE patient placentas showed altered CYP11A1 and autophagy marker expression.
Results: BeWo cells overexpressing CYP11A1 had significantly increased levels of pregnenolone, progesterone, and testosterone. Additionally, the expression levels of autophagy markers in CYP11A1-overexpressing BeWo cells were significantly increased. Trophoblast invasion was significantly reduced in CYP11A1-overexpressing cells as well as in cells treated with high testosterone. This reduction could be significantly rescued when cells were pretreated with flutamide. Overexpression of CYP11A1 in rat pregnancies led to PE-like symptoms and an over-activation of the AR-mediated pathway in the placenta. Elevated expression of CYP11A1 and autophagy markers could also be detected in PE placenta samples.
Conclusions: These results suggest that abnormally high expression of CYP11A1 induces trophoblast autophagy and inhibits trophoblastic invasion, which is associated with the etiology of PE.
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