T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice

Kumfu, Sirinart; Chattipakorn, Nipon; Srichairatanakool, Somdet; Settakorn, Jongkolnee; Fucharoen, Suthat

doi:10.1111/j.1600-0609.2010.01549.x

Cited by 83 publications

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References 39 publications

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“…Studies on cultured cardiomyocytes of heterozygous (Hbb th-3 /Hbb þ ) b-thalassemic mice showed that treatment with a T-type calcium channel (TTCC) blocker and an iron chelator could prevent Fe 2þ uptake into cardiomyocytes, whereas blockers of transferrin receptor1 (TfR1), divalent metal transporter1 (DMT1) and L-type calcium channel (LTCC) could not. 18 However, blockers of TfR1, DMT1, LTCC and TTCC could not prevent Fe 3þ uptake into these cells. 17 These findings suggest that TTCC is an important pathway for Fe 2þ uptake in a cultured thalassemic cardiomyocyte model.…”

Section: /Hbbmentioning

confidence: 97%

“…37 Both in vitro and in vivo studies indicated that heterozygous (Hbb th-3 /Hbb þ ) b-thalassemic mice were anemic, had increased heart weight and cardiac iron accumulation when getting old, and had measurable cardiac dysfunction. [13][14][15][16][17][18][19]30,32,33,[37][38][39][40] Moreover, the homozygous (Hbb th1 / Hbb th1 ), (Hbb d3(th) /Hbb d3(th) ) and heterozygous b-thalassemic mice showed a greater severity of anemia and had higher levels of cardiac iron accumulation than the heterozygous (Hbb th-3 /Hbb þ ) b-thalassemic mice did, even though the mice were still young. [37][38][39] A summary of reports regarding cardiac iron accumulation, cardiac function, and mitochondrial function in b-thalassemic mice (in vivo models) is shown in Table 2.…”

Section: The Hearts Of B-thalassemic Micementioning

confidence: 99%

“…Currently, the model mostly used to study the heart in this condition is the heterozygous (Hbb th-3 /Hbb þ ) b-thalassemic genotype. [14][15][16][17][18][19] Mice heterozygous for the deletion (Hbb th-3 /Hbb þ ) showed characteristics typical of severe thalassemia such as: a significant decrease in hematocrit (Hct), hemoglobin (Hb), red blood cell (RBC) counts, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC), and increased reticulocyte counts, serum bilirubin concentrations, and red cell distribution width (RDW). 13 Heterozygous animals also exhibit bone deformities and splenic enlargement due to increased hematopoiesis which is a typical picture of b-thalassemia, and a spontaneous iron overload in the spleen, liver, and kidneys in this mouse model has been found.…”

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Cardiac complications in beta-thalassemia: From mice to men

Kumfu

Fucharoen

Chattipakorn

2017

Exp Biol Med (Maywood)

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Iron overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. Since investigation of iron overload cardiomyopathy in thalassemia patients has many limitations, a search for an animal model for this condition has been ongoing for decades. In the past decades, there is no doubt that the use of b-thalassemic mice as a study model to investigate the pathophysiology of iron overload cardiomyopathy and the role of various pharmacological interventions, has shed some light in understanding this serious complication and in improving the associated cardiac dysfunction. In this review, the effects of iron overload on the hearts of b-thalassemic mice under conditions of iron overload as well as the efficacy of pharmacological interventions to combat these adverse effects on the heart are reviewed and discussed. AbstractBeta-thalassemia is an inherited hemoglobin disorder caused by reduced or absent synthesis of the beta globin chains of hemoglobin. This results in variable outcomes ranging from clinically asymptomatic to severe anemia, which then typically requires regular blood transfusion. These regular blood transfusions can result in an iron overload condition. The iron overload condition can lead to iron accumulation in various organs, especially in the heart, leading to iron overload cardiomyopathy, which is the major cause of mortality in patients with thalassemia. In the past decades, there is no doubt that the use of b-thalassemic mice as a study model to investigate the pathophysiology of iron overload cardiomyopathy and the role of various pharmacological interventions, has shed some light in understanding this serious complication and in improving the associated cardiac dysfunction. In this review, the effects that iron overload has on the hearts of b-thalassemic mice under conditions of iron overload as well as the efficacy of pharmacological interventions to combat these adverse effects on the heart are reviewed and discussed. The in-depth understanding of biomolecular alterations in the heart of these iron overload thalassemic mice will help give guidance for more effective therapeutic approaches in the near future.

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Section: /Hbbmentioning

confidence: 97%

Section: The Hearts Of B-thalassemic Micementioning

confidence: 99%

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Cardiac complications in beta-thalassemia: From mice to men

Kumfu

Fucharoen

Chattipakorn

2017

Exp Biol Med (Maywood)

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“…Possibilities include L-type Ca 2+ channels, 42 T-type Ca 2+ channels, 43 or perhaps ZIP8, an iron and zinc transporter 39 that was reported to be up-regulated in heart tissue of thalassemic mice. 43 The lack of an effect of iron overload on heart ZIP14 levels might be due to heart-specific regulation or to the comparatively minor degree of iron loading in this tissue. The continued expression of ZIP14 during iron overload suggests that it was at least present to participate in NTBI uptake.…”

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“…Other studies have found that cardiac DMT1 levels were lower in iron-loaded animals than in controls. 44 Recently, Kumfu et al 43 reported that NTBI uptake by cardiomyocytes was unaffected when the iron uptake activity of DMT1 or TfR1 was blocked, indicating that DMT1 and TfR1 are not required for NTBI uptake into these cells. In iron-deficient heart, DMT1 levels were up-regulated 4-fold whereas ZIP14 levels were not affected.…”

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ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders

et al. 2013

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ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n . Collectively, these data suggest that ZIP14 may not only function during iron overload to take up NTBI, but also under normal or iron-deficient conditions when cells take up iron via endocytosis of transferrin. The aim of the present study was to determine how iron deficiency and overload affect the expression of ZIP14 and DMT1 in the liver, pancreas, and heart. The localization of ZIP14 in liver and pancreas was also determined. Knowledge of where ZIP14 is expressed in these organs and how ZIP14 and DMT1 are regulated in vivo by iron will help us to better assess the contribution of these transporters to tissue iron uptake. Design and Methods Animals, diets, and non-heme iron determinationRats were made iron-deficient, iron-adequate, or iron-loaded as described previously. 10 Briefly, weanling (21-day-old) male Sprague-Dawley rats were fed modified AIN-93G purified diets containing iron at 10 ppm (iron deficient, FeD), 50 ppm (iron adequate, FeA), or 18,916 ppm (iron overload, FeO) for 3 weeks. Male Zip14 (Slc39a14) knockout and wild-type control mice maintained on the 129+Ter/SvJcl x C57BL/6 background 11 were analyzed at 6 weeks of age. Male and female hypotransferrinemic (hpx) mice and wild-type controls maintained on the BALB/cJ background were analyzed at 16 weeks of age. Homozygous hpx mice were given a weekly intraperitoneal injection of human apo-transferrin (0.6-1.8 mg) (EMD Chemicals). All mice consumed a commercial rodent diet containing 240 ppm iron (Teklad 7912, Harlan Laboratories). At the end of the studies, animals were anesthetized with vaporized isoflurane and sacrificed by exsanguination via the descending aorta. Tissues were harvested, immediately frozen in liquid nitrogen, and stored at -80°C until use. Animal protocols were approved by the University of Florida Institutional Animal Care and Use Committee. Tissue non-heme iron concentrations were determined colorimetrically after acid digestion of tissues. 12 Generation of ZIP14 antibodyRabbit anti-ZIP14 antiserum was generated against peptide ENEQTEEGKPSAIEVC corresponding to amino acids 138-153 of rat ZIP14. Antibodies specific to the ZIP14 peptide immunogen were affinity purified by using a peptide-agarose column of SulfoLink coupling gel (Pierce). Sample preparation and western blot analysisThe preparation of samples and western blot analysis are described in the Online Supplementary Design and Methods. Transfection, immunoprecipitation, and enzymatic deglycosylationEffectene reagent (Qiagen) was used to transiently transfect HEK 293T cells with either empty pCMV-Sport2 (control) or pCMV-Sport6 containing rat ZIP14 cDNA. To immunoprecipitate ZIP14, anti-ZIP14 antibody (400 mg) was covalently linked to AminoLink Plus Coupling Resin (Thermo Scientific) and added to a Pierce Spin Column according to the manufacturer's protocol. Immunoprecipitations were performed using the CoImmunoprecipitation Kit (Pierce) according to the manufacturer's instructions. To assess protein glycosylati...

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Roles of lipocalin 2 and adiponectin in iron overload cardiomyopathy

Siri‐Angkul

Chattipakorn

2018

Journal Cellular Physiology

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Thalassemia is among the most common genetic diseases worldwide. Ineffective erythropoiesis, chronic hemolysis, and regular blood transfusion in thalassemia patients lead to increased iron burden. Iron overload cardiomyopathy is the most severe co-morbidity and most common cause of mortality in thalassemia patients. Although its associated mechanisms are still not completely understood, cellular iron mishandling, chronic inflammation, and oxidative stress appear to be the key processes involved. In order to acquire a more comprehensive insight of the impact of cardiac iron overload, these alterations need to be intensively investigated. This comprehensive mini-review focuses on two emergent molecules which have been shown to potentially play significant roles in iron overload cardiomyopathy. These two molecules are an iron-transporting protein, lipocalin 2, and an anti-inflammatory adipokine, adiponectin. Reports from in vitro and in vivo studies are comprehensively summarized. Clinical studies examining the roles of these molecules in thalassemia patients are also presented and discussed.

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T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice

Abstract: Our findings indicated that iron uptake mechanisms in cultured thalassemic cardiomyocytes are mainly mediated by TTCC, suggesting that TTCC is the important pathway for iron uptake in this cultured thalassemic cardiomyocyte model.

Cited by 83 publications

References 39 publications

Cardiac complications in beta-thalassemia: From mice to men

Cardiac complications in beta-thalassemia: From mice to men

ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders

Roles of lipocalin 2 and adiponectin in iron overload cardiomyopathy

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