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Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis

ABSTRACT: Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis

PROVIDER: PRJNA708225 | ENA |

REPOSITORIES: ENA

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Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis

Project description:In plasma, iron is normally bound to transferrin, but in conditions of iron overload when the iron-binding capacity of transferrin is exceeded, non-transferrin-bound iron (NTBI) appears in plasma. NTBI is taken up by hepatocytes and other parenchymal cells via NTBI transporters and can cause cellular damage by promoting the generation of reactive oxygen species. However, how NTBI affects endothelial cells, the most proximal cell type exposed to circulating NTBI, has not been explored. We modeled in vitro the effects of systemic iron overload on endothelial cells by treating primary human umbilical vein endothelial cells (HUVECs) with NTBI (ferric ammonium citrate, FAC). Using an unbiased approach, we showed by RNA-Seq that iron loading alters lipid homeostasis in HUVECs by inducing SREBP2-mediated cholesterol biosynthesis. We also determined that FAC increased the susceptibility of HUVECs to apoptosis induced by TNFα. Moreover, we showed that cholesterol biosynthesis contributes to iron-potentiated apoptosis. Treating HUVECs with a cholesterol chelator hydroxypropyl-β-cyclodextrin demonstrated that depletion of cholesterol was sufficient to rescue HUVECs from TNFa-induced apoptosis, even in the presence of FAC. Finally, we showed that FAC or cholesterol treatment modulated the TNFα pathway by inducing novel proteolytic processing of TNFR1 to a short isoform that localizes to lipid rafts. Our study raises the possibility that iron-mediated toxicity in human iron overload disorders is at least in part dependent on alterations in cholesterol metabolism in endothelial cells, increasing their susceptibility to apoptosis.

2021-09-01 | GSE168534 | GEO

Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis.

Project description: Not available

| S-EPMC8463868 | biostudies-literature

Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

Project description:Because iron is essential for a healthy pregnancy, iron supplementation during pregnancy is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and so may overestimate iron stores during inflammation or infection. We used mouse models to determine whether maternal iron loading, inflammation, or their interaction caused poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, caused embryo malformations and demise. Maternal iron excess potentiated embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction was dependent on TNFα signaling, caused apoptosis of the placental and embryo endothelium, and was prevented by anti-TNFα or antioxidant treatment in vivo. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy.

2021-05-17 | GSE153528 | GEO

Transcriptome analysis of IEC4.1 cells in response to TNFα stimulation.

Project description:Mouse intestinal epithelial cells (IEC4.1 cells) were stimulated with TNFα (10 ng/ml) for 4h. The Agilent SurePrint G3 Mouse Gene Expression Microarray (G4852A) was used for the analysis, which provides full coverage of genes and transcripts with the most up-to-date content, including mRNAs and lincRNAs (http://www.chem.agilent.com/store/en_US/Prod-G4852A/G4852A). IEC4.1 cells were grown to 80% confluence for four groups: the siRNA control (Group A, cells treated with a non-specific scrambied siRNA control), the TNFα -stimulated (Group B, cells treated with the siRNA control plus TNFα stimulation), lincRNA-Cox2 siRNA (Group C, cells treated with an siRNA to lincRNA-Cox2), and lincRNA-Cox2 siRNA/ TNFα stimulated (Group D, cells treated with the lincNRA-Cox2 siRNA plus TNFα stimulation). Cells were treated with the siRNAs for 24h, followed by additional culture for 4h in the presence or absence of TNFα (10 ng/ml). Total RNAs were prepared with the RNeasy Mini kit (Qiagen) according to the manufacturer’s instruction (Ambion).

2016-10-25 | E-MTAB-3904 | biostudies-arrayexpress

Molecular mechanisms vascular smooth muscle cell (VSMC) acquisition of macrophage features in response to cholesterol loading

Project description:In this study, murine primary aortic smooth muscle cells (SMCs) were transcriptionally profiled at baseline, after 3 d of cholesterol loading, and after 3 d of subsequent cholesterol unloading with HDL treatment, to identify vascular SMC genes that are transcripionally dysregulated in response to cholesterol loading and/or unloading.

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Next Generation Sequencing Facilitates Quantitative Analysis of control, TNFα and TNFα+JNK I treated GSCs Transcriptomes

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ATAC-seq comparatively analyse chromatin accessibility varition of control, TNFα and TNFα+JNK I treated GSCs

Project description:Among 3,673 TNFα-induced gain of accessibility (at least 2 folds of upregulation in TNFα-treated TPC2-4 cells compared with control), and most of the gained peaks were significantly suppressed by JNKi treatment (TPC2-4 TNFα+JNKi/TPC2-4 TNFα, JNKi: JNK-IN-8, a kinase inhibitor specific for JNK (c-Jun N-terminal kinase) that inhibited phosphorylation of c-JUN)

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RNA-seq of primary aortic human endothelial cells before and after TNFα stimulation

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2020-06-01 | E-MTAB-7896 | biostudies-arrayexpress

ATAC-seq of primary mammalian aortic endothelial cells before and after TNFα stimulation

Project description:To identify conserved TNFα-induced changes in chromatin-accessibility in mammals, we performed ATAC-seq in primary vascular endothelial cells (ECs) isolated from the aortas of human (HAEC), mouse (MAEC) and cow (BAEC), before and after TNFα. We overlay our data with multi-species NF-κB binding data and identify multiple modes of NF-κB-chromatin interactions that are conserved during mammalian TNFα response. Our cross-species approach identifies conserved changes in chromatin-accessibility at NF-κB binding sites that are disease-relevant and essential during mammalian acute inflammation.

2020-06-01 | E-MTAB-7878 | biostudies-arrayexpress

Suppression of microRNA-125b in response to IPNV infection which lead to TNFα-mediated apoptosis of viral pathogenesis

Project description:Infectious pancreatic necrosis virus (IPNV) is an aquatic virus that causes acute infection in freshwater and marine fish. The stage-specific expression of TNFα regulates Bad/Bid-mediated apoptosis and RIP1/ROS-mediated secondary necrosis in IPNV-infected fish cells. Using microRNA microarray and real-time quantitative PCR assays, the expression patterns of microRNA were characterized in different replication stages of IPNV or stimulation of LPS. Two-condition experiment, normal vs IPNV-infected cells (at 6, 12 or 24 hr post-infection), or normal vs LPS-stimulated cells (at 6, 12 or 24 h post-treatment).

2011-12-31 | E-GEOD-30262 | biostudies-arrayexpress

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