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Reversal of hemochromatosis by apo-transferrin in non-transfused and transfused Hbbth3/+ (heterozygous b1/ b2 globin gene deletion) mice


Gelderman, Monique P; Baek, Jin Hyen; Yalamanoglu, Ayla; Puglia, Michele; Vallelian, Florence; Burla, Bo; Vostal, Jaroslav; Schaer, Dominik J; Buehler, Paul W (2015). Reversal of hemochromatosis by apo-transferrin in non-transfused and transfused Hbbth3/+ (heterozygous b1/ b2 globin gene deletion) mice. Haematologica, 100(5):611-622.

Abstract

Intermediate beta-thalassemia demonstrates a broad spectrum of sequelae and may require occasional blood transfusions over a lifetime to correct anemia. Iron overload in intermediate beta-thalassemia results from a paradoxical intestinal absorption, iron release from macrophages and hepatocytes, and sporadic transfusions. Pathological iron accumulation in parenchyma is caused by chronic exposure to non-transferrin bound iron (NTBI) in plasma. The iron scavenger and transport protein transferrin (Tf) is a potential treatment being studied for correction of anemia. However, Tf may also function to prevent or reduce iron loading of tissues when exposures to NTBI increase. Here we evaluate the effects of apoTf dosing on tissue iron loading and early tissue pathology in non-transfused and transfused Hbbth3/+ mice. The murine Hbbth3/+ phenotype demonstrates mild to moderate anemia and exhibits consistent tissue iron accumulation in the spleen, liver, kidneys and myocardium. Our results confirmed that chronic apoTf administration resulted in normalization of anemia. Furthermore, we demonstrate normalization of tissue iron content in liver, kidney and heart and attenuation of early tissue changes in non-transfused Hbbth3/+ mice. ApoTf treatment was also found to attenuate transfusion mediated increases in plasma NTBI and asscociated excess tissue iron loading. These therapeutic effects were associated with normalization of Tf saturation and suppressed plasma NTBI. ApoTf treatment was found to modulate a fundamental iron regulatory pathway as evidenced by decreased erythroid Fam132b (erythroferrone) expression, increased liver HAMP expression and plasma hepcidin-25 lelvels and consequently reduced intestinal ferroportin-1 in apoTf treated thalassemic mice.

Abstract

Intermediate beta-thalassemia demonstrates a broad spectrum of sequelae and may require occasional blood transfusions over a lifetime to correct anemia. Iron overload in intermediate beta-thalassemia results from a paradoxical intestinal absorption, iron release from macrophages and hepatocytes, and sporadic transfusions. Pathological iron accumulation in parenchyma is caused by chronic exposure to non-transferrin bound iron (NTBI) in plasma. The iron scavenger and transport protein transferrin (Tf) is a potential treatment being studied for correction of anemia. However, Tf may also function to prevent or reduce iron loading of tissues when exposures to NTBI increase. Here we evaluate the effects of apoTf dosing on tissue iron loading and early tissue pathology in non-transfused and transfused Hbbth3/+ mice. The murine Hbbth3/+ phenotype demonstrates mild to moderate anemia and exhibits consistent tissue iron accumulation in the spleen, liver, kidneys and myocardium. Our results confirmed that chronic apoTf administration resulted in normalization of anemia. Furthermore, we demonstrate normalization of tissue iron content in liver, kidney and heart and attenuation of early tissue changes in non-transfused Hbbth3/+ mice. ApoTf treatment was also found to attenuate transfusion mediated increases in plasma NTBI and asscociated excess tissue iron loading. These therapeutic effects were associated with normalization of Tf saturation and suppressed plasma NTBI. ApoTf treatment was found to modulate a fundamental iron regulatory pathway as evidenced by decreased erythroid Fam132b (erythroferrone) expression, increased liver HAMP expression and plasma hepcidin-25 lelvels and consequently reduced intestinal ferroportin-1 in apoTf treated thalassemic mice.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
04 Faculty of Medicine > Institute of Evolutionary Medicine
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:23 January 2015
Deposited On:05 Mar 2015 15:07
Last Modified:08 Dec 2017 12:08
Publisher:Ferrata Storti Foundation
ISSN:0390-6078
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.3324/haematol.2014.117325
PubMed ID:25616571

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