Oxidative stress-induced C/EBPβ inhibits β-catenin signaling molecule involving in the pathology of preeclampsia

Zhuang, Baimei; Luο, Xingguang; Rao, Haiying; Li, Q.; Shan, Nan; Liu, X.; Qi, Hongbo

doi:10.1016/j.placenta.2015.06.016

Cited by 46 publications

(31 citation statements)

References 41 publications

(33 reference statements)

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“…FA oxidation is the major source of reactive oxygen species (ROS), and thus aberrant elevation of FA oxidation may result in bursts of ROS generation. Our group and others have shown that oxidative stress inhibits trophoblast invasion [44,51]. Therefore, excessive FA oxidation may impair trophoblast invasion through ROS production.…”

Section: Discussionmentioning

confidence: 83%

“…Although various in vitro and in vivo models have been used to study the etiology of PE [38][39][40], such as exposure of trophoblast cells to hypoxia and hypoxia/reoxygenation [41][42][43][44], induction of 'PE-like' trophoblast cell metabolic alterations had not previously been demonstrated. Our data show that persistent exposure to 1% oxygen for 24 h was required to activate AMPK in HTR8/SVneo cells, indicating that trophoblast cells were resistant to low oxygenation.…”

Section: Discussionmentioning

confidence: 99%

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AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

Yang

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Preeclampsia (PE) has long been assumed to be an ischemic disease of the placenta, although there is limited evidence as to how the ischemia impacts on the placenta. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism and plays an important role in a variety of ischemic diseases by enhancing energy production. The present study investigated placental metabolism in PE, and the role of AMPK in regulating trophoblast function. Methods: placentas from normal and PE complicated pregnancies were subjected to GC-MS to identify fatty acids (FA) metabolic fingerprints, and total FA oxidation was assessed by malondialdehyde (MDA) measurement. The AMPK-ACC signaling pathway was assessed by q-PCR and Western Blotting. HTR8/SVneo trophoblast cultures were exposed to different oxygenation conditions to establish an in vitro PE cell model; further analysis by GC-MS for metabolite profiling was then undertaken. Trophoblasts invasion was assessed by a matrigel transwell assay in the presence/absence of AMPK expression and after manipulations of AMPK activity, and then further validated by human villi outgrowth experiments. Results: AMPK phosphorylation and MDA production were significantly elevated in placentas from pregnancies complicated by PE. Metabolism of cis double bond FA was inhibited while trans double bond FA metabolism was promoted in PE placentas. HTR8/SVneo cell culture conditions of persistent low oxygenation mimicked the hyper-activation of AMPK and enhanced the FA oxidation that was observed in PE. AMPK activation impaired trophoblast invasion, while AMPK inhibition promoted trophoblast invasion. Conclusion: PE complicated placentas are associated with AMPK hyper-activation and consequent alterations in FA oxidation, which inhibit trophoblast invasion.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

Yang

Zhang

et al. 2018

Cell Physiol Biochem

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“…Defective activation of β-catenin during placentation (day 40) in bovine somatic cell nuclear transfer (SCNT)-derived foetuses compromised foetomaternal attachment and exchange and foetal survival, resulting in pregnancy loss [42]. Moreover, recent studies have demonstrated that β-catenin is significantly decreased in preeclamptic placental tissues compared to normal placental controls and that its activation significantly promotes the invasion of HTR-8/SVneo cells [43,44]. Taking into account the initial results, reduced β-catenin expression in the placenta is expected to influence its transcriptional activity and thus the expression of β-catenin response genes, thereby controlling trophoblast invasion.…”

Section: Discussionmentioning

confidence: 99%

Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9

Fan

Hong

et al. 2016

Cell Physiol Biochem

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Background/Aims: Preeclampsia is an idiopathic and serious complication during gestation in which placental trophoblast cells differentiate into several functional subtypes, including highly invasive extravillous trophoblasts (EVTs). Although the cause and pathogenesis of preeclampsia have remained unclear, numerous studies have suggested that the inadequacy of EVT invasion leads to imperfect uterine spiral artery remodelling, which plays a crucial role in the development of preeclampsia. Rac1, or Ras-related C3 botulinum toxin substrate 1, was found to be a key regulator of the migration, invasion uand apoptosis of various tumour cells. Because EVTs share similar invasive and migratory biological behaviours with malignant cells, this study aimed to determine whether the Rac1 signalling pathway affects trophoblast invasion and is thus involved in the pathogenesis of preeclampsia. Methods: We measured the activity of Rac1 and its downstream targets, β-catenin, Snail and MMP9 in placental tissues from patients experiencing a normal pregnancy and those with preeclampsia. Furthermore, we treated HTR-8/SVneo cells with a shRNA Rac1 vector and the β-catenin inhibitor IWP-2 and explored Rac1 signalling pathway activation as well as the effects of Snail and β-catenin on trophoblast invasion. Results: In placental samples from patients experiencing a normal pregnancy and those with preeclampsia, active Rac1 levels and MMP9 protein and mRNA levels were significantly decreased in term pregnancy samples compared to early pregnancy samples. Lower levels were found in preeclampsia samples than in normal term pregnancy samples, and these levels significantly declined in severe preeclampsia samples compared with mild preeclampsia samples. Further analyses demonstrated that both Rac1 shRNA and the β-catenin inhibitor significantly suppressed MMP9 and Snail activation in trophoblasts, thus impairing trophoblast invasion. Notably, silencing Rac1 down-regulated the expression of β-catenin in HTR-8/SVneo cells, demonstrating that β-catenin is a downstream effector of Rac1 in trophoblast invasion. Conclusion: Our data suggest that Rac1-mediated activation of β-catenin might regulate Snail and MMP9 expression subsequently promoting trophoblast invasion in pregnancy.

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“…Furthermore, polyunsaturated diacyl-PCs can promote the oxidation and fragmentation of γ-hydroxyalkenals [29]. Oxidative stress (OS) can occur early in pregnancy [30], induce pregnancy-related disorders like preeclampsia [31][32][33] and preterm premature rupture of membranes [34][35][36], and is considered a detrimental factor in preterm birth pathology [25]. Results of the current study showed that unsaturated diacyl-PCs (PCaaC36:4, PCaaC38:4, PCaaC38:5, PCaaC38:6, PCaaC40:4, PCaaC40:5, PCaaC40:6, PCaaC42:4), especially PCaaC38:6, were negatively correlated with gestational age.…”

Section: Discussionmentioning

confidence: 99%

Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring

Reichetzeder

et al. 2016

Kidney Blood Press Res

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Background/Aims: Preterm birth (PTB) and low birth weight (LBW) significantly influence mortality and morbidity of the offspring in early life and also have long-term consequences in later life. A better understanding of the molecular mechanisms of preterm birth could provide new insights regarding putative preventive strategies. Metabolomics provides a powerful analytic tool to readout complex interactions between genetics, environment and health and may serve to identify relevant biomarkers. In this study, the association between 163 targeted maternal blood metabolites and gestational age was investigated in order to find candidate biomarkers for PTB. Methods: Five hundred twenty-three women were included into this observational study. Maternal blood was obtained before delivery. The concentration of 163 maternal serum metabolites was measured by flow injection tandem mass spectrometry. To find putative biomarkers for preterm birth, a three-step analysis was designed: bivariate correlation analysis followed by multivariable regression analysis and a comparison of mean values among gestational age groups. Results: Bivariate correlation analysis showed that 2 acylcarnitines (C16:2, C2), 1 amino acids (xLeu), 8 diacyl-PCs (PCaaC36:4, PCaaC38:4, PCaaC38:5, PCaaC38:6, PCaaC40:4, PCaaC40:5, PCaaC40:6, PCaaC42:4), and 1 Acylalkyl-PCs (PCaeC40:5) were inversely correlated with gestational age. Multivariable regression analysis confounded for PTB history, maternal body mass index (BMI) before pregnancy, systolic blood pressure at the third trimester, and maternal body weight at the third trimester, showed that the diacyl-PC PCaaC38:6 was the only metabolite inversely correlated with gestational age. Conclusions: Maternal blood concentrations of PCaaC38:6 are independently associated with gestational age.

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Oxidative stress-induced C/EBPβ inhibits β-catenin signaling molecule involving in the pathology of preeclampsia

Cited by 46 publications

References 41 publications

AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9

Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring

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