Autophagy protects against oxidized low density lipoprotein-mediated inflammation associated with preeclampsia

Zhang, Yan; Hu, Xiaoyu; Gao, Guoqiang; Chen, Pingping; Ye, Yuanhua

doi:10.1016/j.placenta.2016.09.015

Cited by 21 publications

(17 citation statements)

References 29 publications

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“…AEA regulates trophoblast differentiation, apoptosis and invasion, and disruption of these tightly coordinated processes is generally associated with placental disorders leading to poor neonatal outcomes (Costa, et al, 2015a;Costa et al, 2015b;Roland et al, 2016;Sitras et al, 2009;Sun, et al, 2010;Zhang et al, 2016). In one study, preeclamptic placentas showed higher expression of n-arachidonyl phosphatidyl ethanolamine phospholipase D an enzyme essential for AEA synthesis, and lower FAAH expression but no change in CB1 or CB2 expression (Aban, et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis

Szilagyi

Composto-Wahler

Joseph

et al. 2019

Pharmacological Research

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The BCRP/ABCG2 efflux transporter is expressed on the membrane of placental syncytiotrophoblasts and protects the fetus from toxicant exposure. Syncytiotrophoblasts arise from the fusion of cytotrophoblasts, a process negatively regulated by the endocannabinoid, anandamide (AEA). It is unknown whether AEA can influence fetal concentrations of xenobiotics by modulating the expression of transporters in syncytiotrophoblasts. Here, we sought to characterize and identify the mechanism(s) responsible for AEA-mediated down-regulation of the BCRP transporter in human placental explants and BeWo trophoblasts. Treatment of human placental explants with AEA (1 μM, 24 h) reduced hCGα, syncytin-1, and BCRP mRNAs by ~30%. Similarly, treatment of BeWo trophoblasts with AEA (0-10 μM, 3-24 h) coordinately downregulated mRNAs for hCGβ, syncytin-2, and BCRP. In turn, AEA increased the sensitivity of trophoblasts to the cytotoxicity of mitoxantrone, a known BCRP substrate, and environmental and dietary contaminants including mycoestrogens and perfluorinated chemicals. AEA-treated

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Section: Discussionmentioning

confidence: 99%

Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis

Szilagyi

Composto-Wahler

Joseph

et al. 2019

Pharmacological Research

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“…Moderate autophagy can prevent macrophages and smooth muscle cells (SMCs) from forming foam cells, and stabilizing atherosclerotic plaques [14][15][16]. Increased autophagy can protect cells from inflammatory damage [9,17,18]. However, overstimulation of autophagy results in destabilization of plaques and inflammatory increases in atherosclerosis [19].…”

Section: Introductionmentioning

confidence: 99%

The role of the LncRNA-FA2H-2-MLKL pathway in atherosclerosis by regulation of autophagy flux and inflammation through mTOR-dependent signaling

et al. 2019

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Atherosclerosis is a progressive, chronic inflammation in arterial walls. Long noncoding RNAs (lncRNAs) participate in inflammation, but the exact mechanism in atherosclerosis is unclear. Our microarray analyses revealed that the levels of lncRNA-FA2H-2 were significantly decreased by oxidized low-density lipoprotein (OX-LDL). Bioinformatics analyses indicated that mixed lineage kinase domain-like protein (MLKL) might be regulated by lncRNA-FA2H-2. In vitro experiments showed that lncRNA-FA2H-2 interacted with the promoter of the MLKL gene, downregulated MLKL expression, and the binding sites between −750 and 471 were necessary for lncRNA-FA2H-2 responsiveness to MLKL. Silencing lncRNA-FA2H-2 and overexpression of MLKL could activate inflammation and inhibited autophagy flux. Both lncRNA-FA2H-2 knockdown and overexpression of MLKL could significantly aggravate inflammatory responses induced by OX-LDL. We found that the 3-methyladenine (3-MA) and Atg7-shRNA enhanced inflammatory responses induced by knockdown of lncRNA-FA2H-2 and overexpression of MLKL. We demonstrated that the effects of MLKL on autophagy might be associated with a mechanistic target of rapamycin (mTOR)-dependent signaling pathways. In vivo experiments with apoE knockout mice fed a western diet demonstrated that LncRNA-FA2H-2 knockdown decreased microtubuleassociated expression of microtubule-associated protein 1 light chain 3 II and lysosome-associated membrane protein 1, but increased expression of sequestosome 1 (p62), MLKL, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-6 in atherosclerotic lesions. Our findings indicated that the lncRNA-FA2H-2-MLKL pathway is essential for regulation of autophagy and inflammation, and suggested that lncRNA-FA2H-2 and MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.

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“…Previous studies (8,9) have highlighted that the oxidation of low-density lipoprotein (LdL) leads to upregulation of the levels of inflammatory factors, including tumor necrosis factor-α and interleukin-6, in the body, and may decrease the cell invasive ability of trophoblasts and promote cell apoptosis, thereby resulting in abnormal development of placenta and the occurrence of PE. According to the National center for Biotechnology Information (NcBI) database, LdL receptor-related protein 6 (LRP6) is highly expressed in placental tissues.…”

Section: Introductionmentioning

confidence: 99%

LRP6 is involved in the proliferation, migration and invasion of trophoblast cells via miR‑346

Zhang

et al. 2020

Int J Mol Med

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Low-density lipoprotein receptor-related protein 6 (LRP6) promotes metastasis in numerous types of cancer; however, its role in trophoblast cells has been less frequently reported. In the present study, the effects of up-and downregulation of LRP6 on trophoblast cells were investigated accordingly. The study aimed to develop a therapeutic target for gestational choriocarcinoma. The expression levels of LRP6 in pre-eclampsia (PE) tissues, trophoblast cell lines and gestational choriocarcinoma cells were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPcR) assay. double-luciferase reporter analysis was conducted to detect the regulatory gene of LRP6. Furthermore, the proliferative, migratory and invasive abilities of trophoblasts and gestational choriocarcinoma cells were determined by ccK-8, wound healing, and Transwell assays, respectively. The expression levels of the genes and proteins of interest [matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2] associated with tumor cell invasion were measured by performing RT-qPcR and western blotting, respectively. The National center for Biotechnology Information database revealed that LRP6 was relatively highly expressed in placental tissues, but was poorly expressed in PE tissues and trophoblast cell lines. The upregulation of LRP6 not only increased the activity, migration and invasion of trophoblast cells, but it also promoted the expression of MMP-2 and MMP-9, whereas it inhibited the expression levels of TIMP-1 and TIMP-2. Such results followed the opposite trend to those of downregulation of LRP6 in gestational choriocarcinoma cells. Moreover, LRP6 was predicted to be the target gene for microRNA (miR)-346, which was highly expressed in PE tissues and trophoblast cell lines. The present study also revealed that LRP6 could reverse the effects of miR-346 on the proliferation, migration and invasion of trophoblast cells. Therefore, considered collectively, the results of the present study have demonstrated that LRP6 is involved in the proliferation, migration and invasion of trophoblast cells via miR-346, and that LRP6 may serve as a potential target in cancer treatment.

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Autophagy protects against oxidized low density lipoprotein-mediated inflammation associated with preeclampsia

Cited by 21 publications

References 29 publications

Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis

Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis

The role of the LncRNA-FA2H-2-MLKL pathway in atherosclerosis by regulation of autophagy flux and inflammation through mTOR-dependent signaling

LRP6 is involved in the proliferation, migration and invasion of trophoblast cells via miR‑346

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