Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1

Ludwiczek, Susanne; Theurl, Igor; Muckenthaler, Martina U.; Jakab, Martin; Mair, Stefan; Theurl, Milan; Kiss, Judit; Paulmichl, Markus; Hentze, Matthias W.; Ritter, Markus; Weiss, Günter

doi:10.1038/nm1542

Cited by 146 publications

(111 citation statements)

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“…3,22 The pathological accumulation of iron in multiple tissues observed in iron overload conditions is thought to be caused by excessive influx of iron into plasma, as well as unbalanced erythrophagocytosis by reticuloendothelial cells in spleen and liver that lead to persistently high circulating NTBI levels which are responsible for the systemic iron dispersal. The hypothesis that tissue iron overload is caused by NTBI is largely based on the assumption that NTBI is randomly transported into cells by unregulated mechanisms, presumably via non-specific divalent cation transporters 23,24 or calcium channels, [25][26][27] subsequent to extracellular reduction of iron(III) to iron(II) by a cell-surface iron reductase such as Dcytb. Chronic exposure of cells in vitro to artificial iron complexes that presumably mimic NTBI (usually ferric citrate) [10][11][12]28,29 has been shown to generate cellular iron overload as indicated by increased ferritin levels, ROS generation, protein and DNA oxidation, and other indicators of cell damage.…”

Section: Discussionmentioning

confidence: 99%

“…29,30 Despite these limitations, attempts have been made to assess NTBI transport by using NTBI-simulating complexes of radiolabeled iron in protein free settings and by artificial inclusion of reductants in order to render the iron transportable by various voltage activatable Ca channels [25][26][27] or by a putative Zn transporter. 23,24 The pathophysiological significance of such approaches is still a subject of debate, and likewise the effects of Ca-channel blockers on ironassociated cardiac damage. 27 Considering the complex nature of plasma NTBI, we choice to use native NTBI containing sera from hypertransfused thalassemia major patients in conjunction with two major strategies for tracing iron ingress into cell compartments.…”

Section: Discussionmentioning

confidence: 99%

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The role of endocytic pathways in cellular uptake of plasma non-transferrin iron

Sohn¹,

Ghoti²,

Breuer³

et al. 2011

Haematologica

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The role of endocytic pathways in cellular uptake of plasma non-transferrin iron

Sohn¹,

Ghoti²,

Breuer³

et al. 2011

Haematologica

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“…20 The following primers and TaqMan probes were used: (1) human: ferroportin: 5Ј-TGACCAGGGCGGGAGA-3Ј (600 nM), 5Ј-GAGGTCAG-GTAGTCGGCCAA-3Ј (600 nM), FAM-CACAACCGCCAGAGAGGAT-GCTGTG-BHQ1 (200 nM); DMT-1ire: 5Ј-GTGGTCAGCGTGGCT-TATCTG-3Ј (600 nM), 5Ј-GGCCTTTAGAGATGCTTACCGTAT-3Ј (600 nM), FAM-TGTTCTACTTGGGTTGGCAATGTTTGATTGC-BHQ1 (200 nM); (2) rat: ferroportin: 5Ј-TTGGTGACTGGGTGGATAAGAA-3Ј (600 nM), 5Ј-CCGCAGAGAATGACTGATACATTC-3Ј (600 nM), FAM-CAGACTTAAAGTGGCCCAGACGTCCCTG-BHQ1 (200 nM); DMT1ire: 5Ј-GCCTGTCGTTCCTGGACTGT-3Ј (600 nM), 5Ј-AGTATTGC-CACCGCTGGTATCT-3Ј (600 nM), FAM-CGGTAAGCATCTCTAAAGT-BHQ1 (200 nM); TfR-1: 5Ј-ATGAGGAACCAGACCGCTACA-3Ј (600 nM), 5Ј-CCACACTGGACTTCGCAACA-3Ј (900 nM), FAM-CCAAGCGTCTCTCTGGGCTCCTACTACA-BHQ1 (300 nM); hepcidin: 5Ј-TGAGCAGCGGTGCCTATCT-3Ј (200 nM), 5Ј-CCATGCCAAGGCT-GCAG-3Ј (600 nM), FAM-CGGCAACAGACGAGACAGACTACGGC-BHQ1 (500 nM)); bGus: 5Ј-ATTACTCGAACAATCGGTTGCA-3Ј (200 nM), 5Ј-GACCGGCATGTCCAAGGTT-3Ј (600 nM), FAM-CG-TAGCGGCTGCCGGTACCACT-BHQ1 (500 nM).…”

Section: Rna Preparation From Tissue Reverse Transcription and Taqmmentioning

confidence: 99%

“…21 Anti-TfR1 antibody (0.5 g/mL; Zymed Laboratories, South San Francisco, CA), antiferritin antibody (2 g/mL; Dako North America, Carpinteria, CA), anti-rat ferroportin antibody, 21 anti-rat DMT-1 antibody, 21 or antiactin (2 g/mL; Sigma Chemie, Deisenhofen, Germany) was used as described. 20 …”

Section: Western Blottingmentioning

confidence: 99%

Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications

Theurl

Aigner

Theurl

et al. 2009

Blood

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The anemia of chronic disease (ACD) is characterized by macrophage iron retention induced by cytokines and the master regulator hepcidin. Hepcidin controls cellular iron efflux on binding to the iron export protein ferroportin. Many patients, however, present with both ACD and iron deficiency anemia (ACD/IDA), the latter resulting from chronic blood loss. We used a rat model of ACD resulting from chronic arthritis and mimicked ACD/IDA by additional phlebotomy to define differing iron-regulatory pathways. Iron retention during inflammation occurs in macrophages and the spleen, but not in the liver. In rats and humans with ACD, serum hepcidin concentrations are elevated, which is paralleled by reduced duodenal and macrophage expression of ferroportin. Individuals with ACD/IDA have significantly lower hepcidin levels than ACD subjects, and ACD/IDA persons, in contrast to ACD subjects, were able to absorb dietary iron from the gut and to mobilize iron from macrophages. Circulating hepcidin levels affect iron traffic in ACD and ACD/IDA and are more responsive to the erythropoietic demands for iron than to inflammation. Hepcidin determination may aid to differentiate between ACD and ACD/IDA and in selecting appropriate therapy for these patients. IntroductionThe anemia of chronic disease (ACD), also termed the "anemia of inflammation," is the most prevalent anemia in hospitalized patients. 1,2 ACD develops in subjects with diseases involving acute or chronic immune activation, such as patients with infections, malignancies, or autoimmune disorders. At least 3 major immunitydriven mechanisms contribute to the anemia of ACD.First, the retention of iron within the mononuclear phagocytic system leads to hypoferremia and subnormal saturation of transferrin, resulting in a limited availability of iron for erythroid progenitor cells or "functional iron deficiency." 1,3,4 Second, cytokines, such as tumor necrosis factor-␣, interferon-␥, and interleukin-1 (IL-1), exert a negative impact on the proliferation and differentiation of erythroid progenitor cells and can induce apoptosis. 5 Third, patients with ACD display an impaired response to erythropoietin (EPO). 6 The functional iron deficiency present in patients with ACD can be complicated by true iron deficiency resulting from chronic blood loss. 7 Differentiation between ACD and ACD/iron deficiency anemia (IDA) is clinically important because iron supplementation is beneficial for ACD/IDA patients but may be deleterious for ACD patients, especially if these subjects have underlying infections or malignancies. 1 In clinical practice, however, differentiating between ACD and ACD/IDA is difficult, as both diseases present with decreased serum iron concentration and transferrin saturation. In addition, ferritin levels are difficult to interpret during inflammation because ferritin expression is induced by both iron overload and inflammatory cytokines. 8 A ratio of soluble transferrin receptor (sTfR)/log ferritin may be useful in distinguishing ACD from ACD/IDA, but the ratio h...

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“…Preparation of total RNA from RAW264.7 macrophages was performed by a guanidinium-isothiocyanate-phenol-chloroformbased extraction method exactly as described [60]. Quantification of mRNA expression was carried out by quantitative real-time PCR following reverse transcription exactly as described [61].…”

Section: Quantitative Real-time Pcr (Q-pcr)mentioning

confidence: 99%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

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In stimulating effector functions of mononuclear phagocytes, IFN-c is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-c is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-c on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-c caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-c exerting a super-inducing effect. This observed regulatory impact of IFN-c reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-a production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-c concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity. IntroductionHost defense against intracellular microbes such as salmonellae or mycobacteria strongly depends on cell-mediated immunity, a major component of which is characterized by interactions between Th1 cells and macrophages [1]. By secreting Th1 cytokines, particularly IFN-c, antigen-specific Th1 cells activate a plethora of microbicidal mechanisms in infected macrophages. Specifically, in mononuclear phagocytes infected with Salmonella enterica serovar typhimurium (S. typhimurium), IFN-c promotes the internalization of bacteria and stimulates their elimination by various mechanisms including reactive oxygen and nitrogen species (ROS and RNS), generated via NADPH phagocyte oxidase and iNOS, respectively [2][3][4][5]. In Salmonella-infected mice, treatment with recombinant IFN-c increases host survival and decreases bacterial numbers in liver and spleen [6]. Conversely, neutralization of murine IFN-c functions with specific antibodies results in reduced host survival and increased bacterial counts [7]. Eur. J. Immunol. 2008. 38: 1923-1936 Immunity to infection In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9]. Iron serves as an essential nutrient for nearly all pathogenic microorganisms, and the expression of iron acquisition systems by infectious agents is associated with their virule...

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Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1

Cited by 146 publications

References 46 publications

The role of endocytic pathways in cellular uptake of plasma non-transferrin iron

The role of endocytic pathways in cellular uptake of plasma non-transferrin iron

Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

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