Iron chelators inhibit human platelet aggregation, thromboxane A<sub>2</sub> synthesis and lipoxygenase activity

Barradas, M.A.; Jeremy, Jamie Y.; Kontoghiorghes, George J.; Mikhailidis, Dimitri P.; Hoflbrand, A.Victor; Dandona, Paresh

doi:10.1016/0014-5793(89)80201-7

Cited by 52 publications

(28 citation statements)

References 21 publications

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“…[33] who have found chelatable iron in gruel from atherosclerotic plaques. This gruel material presumably due to an inhibition of cyclooxygenase or lipooxygenase [36]. has actually been shown to oxidize lipids in vitro.…”

Section: Discussionmentioning

confidence: 97%

Iron and Atherosclerosis: Inhibition by the Iron Chelator Deferiprone (L1)

Matthews¹,

Vercellotti²,

Menchaca³

et al. 1997

Journal of Surgical Research

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Section: Discussionmentioning

confidence: 97%

Iron and Atherosclerosis: Inhibition by the Iron Chelator Deferiprone (L1)

Matthews¹,

Vercellotti²,

Menchaca³

et al. 1997

Journal of Surgical Research

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“…TNF could stimulate the release of iron from a heme protein or from the mitochondrial redox chain. Alternatively, 5-lipoxygenase may be involved, since this enzyme requires DFO-chelatable, redox-active iron and leads to the generation of lipid peroxides (60). Interestingly, this enzyme has been implicated in TNF-mediated cytotoxicity (61) and also in NF-B activation by CD28 in primary T cells (11).…”

Section: Discussionmentioning

confidence: 99%

Lipid Peroxidation Is Involved in the Activation of NF-κB by Tumor Necrosis Factor but Not Interleukin-1 in the Human Endothelial Cell Line ECV304

Bowie¹,

Moynagh²,

O’Neill³

1997

Journal of Biological Chemistry

177

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It has been proposed that reactive oxygen species, and in particular H 2 O 2 , may be involved in the activation of NF-B by diverse stimuli in different cell types. Here we have investigated the effect of a range of putative antioxidants on NF-B activation by interleukin-1 and tumor necrosis factor as well as the ability of H 2 O 2 to activate NF-B in primary human umbilical vein endothelial cells and the transformed human endothelial cell line ECV304. Activation of NF-B and stimulation of IB␣ degradation by H 2 O 2 was only evident in the transformed cells and required much longer contact times than that observed with interleukin-1 or tumor necrosis factor. Furthermore, only H 2 O 2 was sensitive to Nacetyl-L-cysteine, and no increase in H 2 O 2 was detected in response to either cytokine. Pyrrolidine dithiocarbamate has been purported to be a specific antioxidant inhibitor of NF-B that acts independently of activating agent or cell type. However, we found that tumor necrosis factor-but not interleukin-1-driven NF-B activation and IB␣ degradation were sensitive to pyrrolidine dithiocarbamate in transformed cells, while neither pathway was inhibited in primary cells. Phorbol ester-mediated activation was sensitive in both transformed and primary cells. Other antioxidants failed to inhibit either cytokine, while the iron chelators desferrioxamine and 2,2,6,6-tetramethylpiperidine-1-oxyl mimicked the pattern of inhibition seen for the dithiocarbamate. This suggested that pyrrolidine dithiocarbamate was inhibiting NF-B activation in endothelial cells primarily through its iron-chelating properties. Tumor necrosis factor, but not interleukin-1, was found to induce lipid peroxidation in ECV304 cells. This was inhibited by pyrrolidine dithiocarbamate and desferrioxamine. t-Butyl hydroperoxide, which induces lipid peroxidation, activated NF-B. Finally, butylated hydroxyanisole, which inhibits lipid peroxidation but has no iron-chelating properties, inhibited NF-B activation by tumor necrosis factor but not interleukin-1.Taken together, the results argue against a role for H 2 O 2 in NF-B activation by cytokines in endothelial cells. Furthermore, tumor necrosis factor and interleukin-1 activate NF-B through different mechanisms in ECV304 cells, with the tumor necrosis factor pathway involving iron-catalyzed lipid peroxidation.The inducible, higher eukaryotic transcription factor NF-B has an important role in the regulation of a number of genes involved in immune and inflammatory responses. It is activated in many cell types by a wide range of stimuli including the proinflammatory cytokines interleukin-1 (IL-1) 1 and tumor necrosis factor (TNF) and the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) (reviewed in Ref. 1).In endothelial cells (ECs), activation of NF-B is central to the regulation of many genes by IL-1 and TNF such as the cell adhesion molecules vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin (2) and tissue factor (3). Recently, NF-B has been identified ...

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“…DFO chelates lysosomal iron, which should be present at a different location in the cell, promoting L-ROS production. In addition, lipophilic iron chelators are able to cross membranes and chelate the labile iron pool, which is critical for the fragmentation and peroxidation of PUFAs (22,23,52). Excess active iron donates electrons to generate ROS based on the Fenton reaction, promoting lipid peroxidation and the initiation of ferroptosis (54).…”

Section: Ferroptosis Is Induced By Lipid Peroxidation Cell Lines Selmentioning

confidence: 99%

Metabolic networks in ferroptosis (Review)

et al. 2018

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Abstract.Ferroptosis is an iron-dependent and peroxidation-driven form of cell death associated with multiple metabolic disorders and disrupted homeostasis. A number of metabolic processes and homeostasis are affected by ferroptosis. The molecules that regulate ferroptosis are involved in metabolic pathways that regulate cysteine exploitation, glutathione state, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation and iron homeostasis. The present review summarizes the metabolic networks involved in ferroptosis based on previous studies, and discusses the function of ferroptosis in pathological processes, including cancer. Finally, the clinical significance of ferroptosis is highlighted, to provide evidence for further studies.

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Iron chelators inhibit human platelet aggregation, thromboxane A₂ synthesis and lipoxygenase activity

Cited by 52 publications

References 21 publications

Iron and Atherosclerosis: Inhibition by the Iron Chelator Deferiprone (L1)

Iron and Atherosclerosis: Inhibition by the Iron Chelator Deferiprone (L1)

Lipid Peroxidation Is Involved in the Activation of NF-κB by Tumor Necrosis Factor but Not Interleukin-1 in the Human Endothelial Cell Line ECV304

Metabolic networks in ferroptosis (Review)

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Iron chelators inhibit human platelet aggregation, thromboxane A2 synthesis and lipoxygenase activity

Cited by 52 publications

References 21 publications

Iron and Atherosclerosis: Inhibition by the Iron Chelator Deferiprone (L1)

Iron and Atherosclerosis: Inhibition by the Iron Chelator Deferiprone (L1)

Lipid Peroxidation Is Involved in the Activation of NF-κB by Tumor Necrosis Factor but Not Interleukin-1 in the Human Endothelial Cell Line ECV304

Metabolic networks in ferroptosis (Review)

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Iron chelators inhibit human platelet aggregation, thromboxane A₂ synthesis and lipoxygenase activity