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PubMed: 29212341

Title
Scavenging Reactive Oxygen Species Production Normalizes Ferroportin Expression and Ameliorates Cellular and Systemic Iron Disbalances in Hemolytic Mouse Model.
Journal
Antioxidants & redox signaling
Volume
29
Issue
None
Pages
484-499
Date
2018-08-10
Authors
Alan B | Lai D | Leopold K | Tangudu NK | Vettorazzi S | Vinchi F | Vujić Spasić M | Wörle K

Evidence 2e71e8da61
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Expectedly, and in line with previous report (13), treatment of macrophages with DFO abolished ferroportin and ferritin induction by heme, whereas TfR1 expression was lowered upon heme and combined treatment with heme and DFO (Fig. 7D).

a(CHEBI:"desferrioxamine B") decreases p(MGI:Slc40a1) View Subject | View Object

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a(CHEBI:"desferrioxamine B") decreases p(MGI:Ftl1) View Subject | View Object

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complex(a(CHEBI:"desferrioxamine B"), a(CHEBI:heme)) decreases p(MGI:Tfrc) View Subject | View Object

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Evidence 07c14c51a0
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We confirmed that the redox active iron, which is derived from heme catabolism in macrophages, is capable of catalyzing ROS formation (Fig. 7A) (19).

a(CHEBI:"iron(2+)") increases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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Evidence 6528de711f
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Under heme overload conditions, macrophages acquire an iron phenotype characterized by low intracellular iron and high ferroportin expression.

a(CHEBI:"iron(2+)") negativeCorrelation a(CHEBI:heme) View Subject | View Object

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a(CHEBI:heme) positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

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a(CHEBI:heme) negativeCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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p(MGI:Slc40a1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 436fca6010
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These data suggested that during severe hemolysis, heme mediated ferroportin induction and low hepcidin in HbS mice (11) served to elevate systemic iron availability, required to sustain high erythropoietic demands in these mice.

a(CHEBI:"iron(2+)") positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

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a(CHEBI:heme) positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

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p(MGI:Slc40a1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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p(MGI:Slc40a1) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Evidence 89f1e1446d
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We showed that simulation of macrophages with LPS resulted in significant reduction in ferroportin mRNA and protein expression and enhanced intracellular iron deposition throughout all time points tested (Fig. 5A–D).

a(CHEBI:"iron(2+)") positiveCorrelation a(CHEBI:lipopolysaccharide) View Subject | View Object

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a(CHEBI:lipopolysaccharide) negativeCorrelation r(MGI:Slc40a1) View Subject | View Object

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a(CHEBI:lipopolysaccharide) negativeCorrelation p(MGI:Slc40a1) View Subject | View Object

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a(CHEBI:lipopolysaccharide) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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p(MGI:Slc40a1) negativeCorrelation a(CHEBI:lipopolysaccharide) View Subject | View Object

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r(MGI:Slc40a1) negativeCorrelation a(CHEBI:lipopolysaccharide) View Subject | View Object

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Evidence 32bcd58252
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This dramatically contrasts the iron phenotype that develops in response to LPS, hallmarked by high intracellular iron levels and low ferroportin expression (10, 20, 48).

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a(CHEBI:lipopolysaccharide) negativeCorrelation p(MGI:Slc40a1) View Subject | View Object

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a(CHEBI:lipopolysaccharide) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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p(MGI:Slc40a1) negativeCorrelation a(CHEBI:lipopolysaccharide) View Subject | View Object

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Evidence 188cfa458b
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We showed that NAC treatment scavenged ROS production and, more importantly, it counteracted ferroportin induction by heme (Fig. 8B, C).

a(CHEBI:acetylcysteine) negativeCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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a(CHEBI:acetylcysteine) decreases p(MGI:Slc40a1) View Subject | View Object

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a(MESH:"Reactive Oxygen Species") negativeCorrelation a(CHEBI:acetylcysteine) View Subject | View Object

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Evidence c444813cb7
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We show that heme, in a concentration range found during hemolytic episodes, increases intracellular ROS production and consequentially signals for ferroportin induction and subsequent iron export from the macrophages.

a(CHEBI:heme) increases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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a(MESH:"Reactive Oxygen Species") increases p(MGI:Slc40a1) View Subject | View Object

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Evidence 9ac6be6c3e
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High ferroportin levels were measured in macrophages upon heme overload and erythrophagocytosis (12, 13, 31, 32, 37) and in hemolytic murine models of b-thalassemia and phenylhydrazineinduced hemolytic anemia (11, 22, 34).

a(CHEBI:heme) positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

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a(HM:erythrophagocytosis) positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

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p(MGI:Slc40a1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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p(MGI:Slc40a1) positiveCorrelation a(HM:erythrophagocytosis) View Subject | View Object

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Evidence 18e586553e
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Our in vivo observations could be recapitulated in isolated macrophages, which upon stimulation with heme (25 lM; 16 h) demonstrated increased ferroportin mRNA and protein expression (Fig. 4A, B) and a significant decrease in the intracellular iron pool (2.2-fold; p < 0.01) (Fig. 4C).

a(CHEBI:heme) positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

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a(CHEBI:heme) positiveCorrelation r(MGI:Slc40a1) View Subject | View Object

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p(MGI:Slc40a1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 735309de3f
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So far, our results established that in the conditions of acute and chronic heme overload, macrophages acquired high ferroportin expression and an efficient iron export.

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p(MGI:Slc40a1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 7f24271b1d
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In a time-line experiment, we showed that heme loading of macrophages decreased the expression of heme–hemopexin complex receptor and transferrin receptor 1 (TfR1) (Fig. 4D), while ferritin levels remained largely unchanged except for an increase in ferritin levels at 16 h post-treatment (Fig. 4D).

a(CHEBI:heme) increases p(MGI:Ftl1) View Subject | View Object

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a(CHEBI:heme) decreases complex(a(CHEBI:heme), p(MGI:Hpx)) View Subject | View Object

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a(CHEBI:heme) decreases p(MGI:Tfrc) View Subject | View Object

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Evidence 7f42e4a77e
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By contrast, treatment of macrophages with PPIX failed to increase the ROS production and ferroportin expression, implying that iron within the heme moiety was required for the observed effects (Fig. 7B).

a(CHEBI:protoporphyrin) causesNoChange a(MESH:"Reactive Oxygen Species") View Subject | View Object

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a(CHEBI:protoporphyrin) causesNoChange p(MGI:Slc40a1) View Subject | View Object

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Evidence 7c3369dba2
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In contrast, PPIX treatment of macrophages was capable of inducing Hmox-1 expression (Fig. 7C), indicating that PPIX was taken up by macrophages and catabolized (13).

a(CHEBI:protoporphyrin) increases p(MGI:Hmox1) View Subject | View Object

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Evidence aa5548b3bf
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Our study provides evidence that the increase in cellular oxidant levels, as a result of NADPH oxidase activity, was responsible for ferroportin induction by heme.

act(a(MESH:"NADPH Oxidase")) positiveCorrelation p(MGI:Slc40a1) View Subject | View Object

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p(MGI:Slc40a1) positiveCorrelation act(a(MESH:"NADPH Oxidase")) View Subject | View Object

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Evidence efe2c20af3
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In parallel to ferroportin, the expression of Hmox-1 was increased by heme-triggered ROS production and its induction was prevented by the combined treatment with NAC and heme (Fig. 8B).

complex(a(CHEBI:acetylcysteine), a(CHEBI:heme)) decreases p(MGI:Hmox1) View Subject | View Object

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Evidence 9c70a719e1
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Similarly, the induction of Hmox1 by heme was abolished by cotreatment with NAC and heme, supporting our in vitro findings (Fig. 8D).

complex(a(CHEBI:acetylcysteine), a(CHEBI:heme)) decreases p(MGI:Hmox1) View Subject | View Object

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Evidence 80f040d42f
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We showed that increase in ferroportin mRNA and protein expression by heme was effectively prevented in mice receiving combined treatment of NAC and heme (Fig. 8D, E).

complex(a(CHEBI:acetylcysteine), a(CHEBI:heme)) decreases r(MGI:Slc40a1) View Subject | View Object

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complex(a(CHEBI:acetylcysteine), a(CHEBI:heme)) decreases p(MGI:Slc40a1) View Subject | View Object

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Evidence f9737c7abc
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We showed that cotreatment of macrophages with heme and apocynin (Fig. 7E), as well as with heme and allopurinol (Fig. 7F), fully prevented ferroportin induction by heme. These data revealed that inhibiting superoxide at its production site is an effective way to counteract heme-mediated ferroportin induction.

complex(a(CHEBI:allopurinol), a(CHEBI:heme)) decreases p(MGI:Slc40a1) View Subject | View Object

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complex(a(CHEBI:apocynin), a(CHEBI:heme)) decreases p(MGI:Slc40a1) View Subject | View Object

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Evidence 8649a5044f
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In addition, ferroportin undergoes post-translational control by the systemic iron regulator, hepcidin, whereby binding of hepcidin to ferroportin causes its internalization and degradation, leading to iron retention within the cells (21, 41).

complex(p(MGI:Hamp), p(MGI:Slc40a1)) increases deg(p(MGI:Slc40a1)) View Subject | View Object

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