Abnormal CYP11A1 gene expression induces excessive autophagy, contributing to the pathogenesis of preeclampsia

Abstract

ObjectiveIn 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 DesignIn 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.ResultsBeWo 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.ConclusionsThese results suggest that abnormally high expression of CYP11A1 induces trophoblast autophagy and inhibits trophoblastic invasion, which is associated with the etiology of PE.

CYP11A1 Upregulation Leads to Trophoblast Oxidative Stress and Fetal Neurodevelopmental Toxicity That can be Rescued by Vitamin D

“…The promoter of the heavy and light strands of the mitochondrial genome is located in this region ( Sharma et al, 2005 ; Barshad et al, 2018 ), indicating that this damage can significantly affect mitochondrial function and cellular metabolic behavior, including mitochondrial genomic mutation, mitochondrial autophagy, and apoptosis. These findings further explain the underlying mechanism of trophoblast cell autophagy and apoptosis, triggered by the upregulation of CYP11A1 ( Pan et al, 2017 ), and contribute to our understanding of the association between CYP11A1 and preeclampsia.…”

“…CYP11A1 has been identified as a candidate pathogenic gene for preeclampsia and shown to be hypomethylated and transcribed at higher levels in women with preeclampsia ( Enquobahrie et al, 2008 ; Hogg et al, 2013 ). Our previous studies have demonstrated that upregulation of CYP11A1 induces trophoblast apoptosis and is positively correlated with liver damage during preeclampsia; however, the underlying mechanism remains elusive ( He et al, 2013 ; Pan et al, 2017 ). In addition, due to the essential roles of steroid hormones in pregnancy, a valid question is whether or not the upregulation of this key gene has other negative effects.…”

Androgens in maternal vascular and placental function: implications for preeclampsia pathogenesis

“…It would be interesting to assess whether compromised expression of aromatase also exists in tissues and organs other than placenta during preeclamptic gestation. A recent study also indicated that overexpression of CYP11A1 mRNA (commonly referred as cholesterol side-chain cleavage enzyme that catalyzes the first steps of steroidogenesis) in human trophoblast cells induces increased testosterone production and preeclampsia-like placental dysfunction that could be reversed with flutamide, an androgen receptor antagonist ( Pan et al 2017 ). Taken together, these findings support the notion that increased testosterone during preeclamptic pregnancies may be of placental origin, although other sources cannot be excluded.…”

“…The reason for smaller placenta in testosterone-exposed dams is not known, but may involve increased apoptosis or decreased proliferation ( Ling et al 2002 ). Pan et al (2017) revealed a critical role for testosterone in human trophoblast invasion and demonstrated that flutamide, an AR antagonist, could rescue testosterone-induced reduction in invasion ( Pan et al 2017 ). It is possible that testosterone-induced autophagy (human) ( Pan et al 2017 ), reduced invasion (human) ( Pan et al 2017 ) or advanced placental differentiation (sheep) ( Veiga-Lopez et al 2011 ), may all contribute to such alterations in placental weight/morphology.…”

The Catalytic Mechanism of Steroidogenic Cytochromes P450 from All-Atom Simulations: Entwinement with Membrane Environment, Redox Partners, and Post-Transcriptional Regulation

“…Pregnenolone, is synthesized in the inner membrane of mitochondria by a complex enzymatic machinery comprising CYP11A1 and its redox partners. CYP11A1 deficiency has been associated with lipoid congenital adrenal hyperplasia, affecting the development of sex characteristics, while its overexpression impairs the placentation process and contributes to the pathogenesis of pre-eclampsia [43]. Pregnenolone biosynthesis occurs in three steps (Figure 4a).…”