Autophagy in the placenta of women with hypertensive disorders in pregnancy

Akaishi, Rina; Yamada, Takahiro; Nakabayashi, Kazuhiko; Nishihara, H. K.; Furuta, Itsuko; Kojima, Takashi; Morikawa, Mamoru; Fujita, Naonobu

doi:10.1016/j.placenta.2014.10.009

Cited by 72 publications

(60 citation statements)

References 18 publications

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“…We summarized the results from studies on autophagy in the placenta from women with preeclampsia and fetal growth restriction (FGR) (Table 1) [9394959697]. Several studies have demonstrated that placenta from women with preeclampsia or FGR showed increased autophagic activity in villous trophoblasts compared with placenta from a normal pregnancy.…”

Section: Part IImentioning

confidence: 99%

“…However, depending on the study population selected in each study, there are some conflicting points. Although some studies indicated that placentas from women with preeclampsia demonstrated increased autophagy regardless of the presence of FGR [94], other studies found that the increased autophagy in placenta was observed only in the group with preeclampsia complicated with FGR but not in the group with only preeclampsia [95]. Nonetheless, it is certain that the severity of preeclampsia or FGR is positively correlated with enhanced autophagosome formation.…”

Section: Part IImentioning

confidence: 99%

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Autophagy in the placenta

Roh

2017

Obstet Gynecol Sci

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Autophagy is an evolutionarily conserved catalytic process by which cytoplasmic components including damaged macromolecules and organelles are degraded. The role of autophagy includes adaptive responses to nutrition deprivation or intracellular stimuli. Although autophagosomes were first observed in early 1960s, it was 1990s that autophagy-related genes in yeast were identified and studied. Nowadays, the molecular machinery of autophagy and signaling pathway to various stimuli are almost outlined. Dysregulation of autophagic activity has been implicated in many human diseases including neurodegenerative diseases, infection and inflammation, and malignancies. However, since current understanding of autophagy in placenta is just at the beginning, this paper aims to provide general information on autophagy (part I) and to summarize articles on autophagy in human placenta (part II). This review article will serve as a basis for further researches on autophagy in relation to human pregnancy and its complications.

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Section: Part IImentioning

confidence: 99%

Section: Part IImentioning

confidence: 99%

Autophagy in the placenta

Roh

2017

Obstet Gynecol Sci

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“…This is in line with previous studies in second trimester and term placenta (Oh et al 2008), suggesting induction of autophagy at all stages of pregnancy. Of note is that a previous correlation analysis suggested decreasing LC3B-II levels with advancing gestational week (Akaishi et al 2014). However, our observation of decreased LC3B-II in first-trimester placenta in response to TNF-α is in stark contrast to a previous study showing increased LC3B-II levels in TNF-α-treated Jeg-3 trophoblast cells (Oh et al 2008).…”

Section: Discussionmentioning

confidence: 91%

“…On the basis of mRNA and protein levels of autophagy markers, such as the posttranslationally modified active form of microtubule-associated protein 1 light chain 3 beta (LC3B-II), lysosome-associated membrane protein 2 (LAMP-2) and beclin-1, increased autophagy is described in placentas from pregnancies complicated by fetal growth restriction, with or without preeclampsia, but not for those with pre-eclampsia alone (Curtis et al 2013; Hung et al 2012). In contrast, other studies showed evidence for increased autophagy in placentas from hypertensive pregnancies, independent of the presence of growth restriction (Akaishi et al 2014; Oh et al 2008). Besides hypertension, maternal body mass index (BMI) and fetal sex seem to influence placental autophagy, as activation of autophagosomal formation and autophagosome–lysosome fusion have been shown in placentas from male but not female offspring of overweight and obese women.…”

Section: Introductionmentioning

confidence: 83%

“…For human placenta, even the mode of delivery seems to influence autophagic activity, with higher levels of autophagy markers in placentas from cesarean section compared to vaginal delivery (Signorelli et al 2011). A substantial body of in vitro experiments using primary trophoblasts and cell lines suggests inflammation and oxidative stress as the underlying stimuli for altered placental autophagy, giving rise to pregnancy pathologies, such as preeclampsia (Akaishi et al 2014; Kalkat et al 2013; Oh et al 2008) and fetal growth restriction (Curtis et al 2013). On the basis of mRNA and protein levels of autophagy markers, such as the posttranslationally modified active form of microtubule-associated protein 1 light chain 3 beta (LC3B-II), lysosome-associated membrane protein 2 (LAMP-2) and beclin-1, increased autophagy is described in placentas from pregnancies complicated by fetal growth restriction, with or without preeclampsia, but not for those with pre-eclampsia alone (Curtis et al 2013; Hung et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Placental DAPK1 and autophagy marker LC3B-II are dysregulated by TNF-α in a gestational age-dependent manner

Prokesch

Blaschitz

Bauer

et al. 2017

Histochem Cell Biol

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Autophagy, a cell-survival process responsible for degradation of protein aggregates and damaged organelles, is increasingly recognized as another mechanism essential for human placentation. A substantial body of experiments suggests inflammation and oxidative stress as the underlying stimuli for altered placental autophagy, giving rise to placenta dysfunction and pregnancy pathologies. Here, the hypothesis is tested whether or not pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α are able to influence the expression profile of autophagy genes in human first-trimester villous placenta. Autophagy-focused qPCR arrays identified substantial downregulation of death-associated protein kinase 1 (DAPK1) in first-trimester placental explants in response to IL-6 and TNF-α, respectively. Immunohistochemistry of placental explants detected considerable DAPK1 staining in placental macrophages, villous cytotrophoblasts and less intense in the syncytiotrophoblast. Both immunohistochemistry and Western blot showed decreased DAPK1 protein in TNF-α-treated placental explants compared to control. On cellular level, DAPK1 expression decreased in SGHPL-4 trophoblasts in response to TNF-α. Observed changes in the expression profile of autophagy-related genes were reflected by significantly decreased lipidation of autophagy marker microtubule-associated protein light chain 3 beta (LC3B-II) in first trimester placental explants in response to TNF-α. Analysis of TNF-α-treated term placental explants showed decreased DAPK1 protein, whereas in contrast to first-trimester LC3B expression and lipidation increased. Immunohistochemistry of placental tissues from early-onset preeclampsia (PE) showed less DAPK1 staining, when compared to controls. Accordingly, DAPK1 mRNA and protein were decreased in primary trophoblasts isolated from early-onset PE, while LC3B-I and -II were increased. Results from this study suggest that DAPK1, a regulator of apoptosis, autophagy and programmed necrosis, decreases in human placenta in response to elevated maternal TNF-α, irrespective of gestational age. In contrast, TNF-α differentially regulates levels of autophagy marker LC3B in human placenta over gestation.

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Overexpression of let‐7b exerts beneficial effects on the functions of human placental trophoblasts by activating the ERK1/2 signaling pathway

Gao

Zhang²,

Meng

2021

Molecular Reproduction Devel

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The present work aimed to explore let-7b's molecular mechanisms that regulate the functions of placental trophoblasts and to examine placental let-7b expression in human pre-eclampsia (PE). Human trophoblast HTR-8/SVneo cells underwent transduction with control and let-7b overexpressing lentiviruses, respectively. Cell proliferation assessment utilized cell counting kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) assays. Apoptosis, autophagy, inflammation, epithelial-to-mesenchymal transition (EMT), and ERK1/2 signaling-associated proteins were assessed by immunoblot. Placental tissue samples were collected from women with normal pregnancy (n = 20) and PE patients (n = 14). Let-7b overexpression in HTR-8/SVneo cells remarkably induced cell proliferation and invasion, suppressed apoptosis and autophagy, and resulted in decreased tumor necrosis factorα (TNF-α) expression and increased interleukin 6 (IL-6) expression in trophoblasts. Notably, the beneficial effects of let-7b overexpression, including cell invasion and EMT, were largely reversed by treatment with U0126, an indirect ERK1/2 signaling inhibitor, in these cells. TGF-β receptor type-1 (TGFBR1) overexpression weakened let-7b's functions in ERK pathway activation and invasion in trophoblasts. Placental tissue specimens from PE cases demonstrated significantly lower let-7b expression compared with normal controls. Overexpression of let-7b exerts beneficial effects on the functions of human placental trophoblasts via ERK1/2 signaling, and placental let-7b is downregulated in human PE. These findings suggest let-7b is a promising biomarker for the prospective diagnosis and targeted therapy of PE.

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Autophagy in the placenta of women with hypertensive disorders in pregnancy

Abstract: Introduction: Autophagy has not been studied extensively in the human placenta. This study was performed to determine whether autophagy is increased in the placentas of women with hypertensive disorders in pregnancy compared to normotensive pregnancies.

Cited by 72 publications

References 18 publications

Autophagy in the placenta

Autophagy in the placenta

Placental DAPK1 and autophagy marker LC3B-II are dysregulated by TNF-α in a gestational age-dependent manner

Overexpression of let‐7b exerts beneficial effects on the functions of human placental trophoblasts by activating the ERK1/2 signaling pathway

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