Removal of erythrocyte membrane iron in vivo ameliorates the pathobiology of murine thalassemia.

Browne, Paul; Shalev, Oded; Kuypers, Frans A.; Brugnara, Carlo; Solovey, Anna; Mohandas, Narla; Schrier, Stanley L.; Hebbel, Robert P.

doi:10.1172/jci119666

Cited by 38 publications

(24 citation statements)

References 26 publications

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“…We measured this parameter by labeling erythrocytes in vivo with NHS-X-biotin. 37 The half-life of normal erythrocytes measured by this method was 18.9 Ϯ 1.9 days (n ϭ 3), a value consistent with that obtained using radiolabeling. 37,38 Survival of erythrocytes in untreated ␤ thalassemic mice was 9.2 Ϯ 1.1 days.…”

Section: Improvement Of Erythropoiesissupporting

confidence: 82%

“…37 The half-life of normal erythrocytes measured by this method was 18.9 Ϯ 1.9 days (n ϭ 3), a value consistent with that obtained using radiolabeling. 37,38 Survival of erythrocytes in untreated ␤ thalassemic mice was 9.2 Ϯ 1.1 days. Survival of erythrocytes was 16.9 days when measured 14 weeks after treatment in mouse 2, whose Hct value was 55.6% at that time.…”

Section: Improvement Of Erythropoiesissupporting

confidence: 82%

“…37 Ten microliters of polystyrene beads (Dynabeads M-450; Dynal, Great Neck, NY) coated with affinity-purified goat antimouse IgG were incubated with 2.5 ϫ 10 5 RBCs for 1 hour, shaking gently at room temperature. The percentage of RBCs with attached beads was determined using direct light microscopy.…”

Section: Membrane-bound Immunoglobulinmentioning

confidence: 99%

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βMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in β thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles

Samakoglu

Fattori

Lamartina

et al. 2001

Blood

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Mechanisms governing the induction of effective erythropoiesis in response to erythropoietin (Epo) oversecretion have been investigated in ␤ thalassemic C57Bl/6 Hbbth mice. Naked DNA encoding an expression vector for mouse Epo was introduced into skeletal muscles by electrotransfer. A transient increase of serum Epo concentrations with a proportional augmentation of hematocrit values was observed. Various parameters relevant to ␤ thalassemia were surveyed in blood samples taken before treatment, at the peak of Epo secretion, and when the phenotype reverted to anemia. We measured globin messenger RNA (mRNA) levels in reticulocytes by real-time quantitative polymerase chain reaction, globin chain synthesis levels, and several indicators of erythrocyte membrane quality, including bound ␣ chains, bound immunoglobulins, main protein components, and iron compartmentalization. Data indicated that high serum Epo levels primarily affect ␤minor-globin mRNA accumulation in reticulocytes. Other changes subsequent to intense Epo stimulation, like increased ␤minor/␣-globin chain synthesis ratio, reduced levels of ␣ chains and immunoglobulins bound to membranes, improved spectrin/band 3 ratio, increased red blood cell survival, and improved erythropoiesis appeared as consequences of increased ␤minor-globin mRNA levels. This conclusion is consistent with models postulating that intense Epo stimulation induces the expansion and differentiation of erythroid progenitors committed to fetal erythropoiesis. Although phenotypic correction was partial in mice, and comparable achievements will probably be more difficult to obtain in humans, naked DNA electrotransfer may provide a safe and low-cost method for reassessing the potentials of Epo as an inducer of fetal erythropoiesis reactivation in patients with ␤ thalassemia. (Blood. 2001;97:2213-2220)

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Section: Improvement Of Erythropoiesissupporting

confidence: 82%

Section: Improvement Of Erythropoiesissupporting

confidence: 82%

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βMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in β thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles

Samakoglu

Fattori

Lamartina

et al. 2001

Blood

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“…Additionally, our finding of elevated apoptosis in MELHO-1 cells is congruent with an earlier report that the inhibition of heme synthesis induces apoptosis in human erythroid progenitor cells. 48 Also, membranes of b-thalassemic erythrocytes, 49,50 and likely also erythroblasts, contain iron-a substrate for a Fenton reaction-that can be derived from heme because of the enhanced activity of HO-1.…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme

Garcia-Santos

Schranzhofer

Horváthová

et al. 2014

Blood

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Key Points• Heme oxygenase-1 levels increase during erythroid differentiation.• Heme oxygenase-1 actively participates in maintaining appropriate hemoglobinization rates.Heme is essential for the function of all aerobic cells. However, it can be toxic when it occurs in a non-protein-bound form; cells maintain a fine balance between heme synthesis and catabolism. The only physiological mechanism of heme degradation is by heme oxygenases (HOs). The heme-inducible isoform, HO-1, has been extensively studied in numerous nonerythroid cells, but virtually nothing is known about the expression and potential significance of HO-1 in developing red blood cells. We have demonstrated that HO-1 is present in erythroid cells and that its expression is upregulated during erythroid differentiation. Overexpression of HO-1 in erythroid cells impairs hemoglobin synthesis, whereas HO-1 absence enhances hemoglobinization in cultured erythroid cells. Based on these results, we conclude that HO-1 controls the regulatory heme pool at appropriate levels for any given stage of erythroid differentiation. In summary, our study brings to light the importance of HO-1 expression for erythroid development and expands our knowledge about the fine regulation of hemoglobin synthesis in erythroid cells. Our results indicate that HO-1 plays an important role as a coregulator of the erythroid differentiation process. Moreover, HO-1 expression must be tightly regulated during red blood cell development. (Blood.

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“…Precipitation and denaturation of the globin chain can result in the liberation of both heme and nonheme irons [55,56]. Redistribution of cellular iron is harmful to the membrane, based on an iron-catalyzed generation of ROS [57]. We found that long-term feeding of the ferrocene diet to the mice increased the amount of normal RBC membrane nonheme iron, but not cytoplasmic ferritin iron.…”

Section: Discussionmentioning

confidence: 89%

Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice

Srichairatanakool¹,

Pangjit²,

Phisalaphong³

et al. 2013

ABB

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Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising effective iron chelatorsfor the treatment of iron overload in -thalassemia patients; nonetheless, their side effects have also been reported. 3-Hydroxypyridinone derivatives are being developed as a safer new chelator and in combined chelation therapy. We evaluated the iron-chelating activity of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in iron-loaded C57BL6 mice. The feeding of a ferrocene-supplemented diet (Fe diet) to mice resulted in iron overload, detectable plasma nontransferrin-bound iron (NTBI) and labile plasma iron (LPI), and increases of red cell membrane iron, plasma malondialdehyde (MDA) and excessive tissue iron deposits. Like DFP, the CM1 lowered the levels of the membrane non-heme iron, the NTBI and LPI (p < 0.05) and the MDA after 3 months of treatment. Administration of the Fe diet and the Fe diet along with the chelators did not change the morphology of the liver and heart. Numerous iron accumulations were observed in the liver and spleen tissues of the Fe dietfed mice, whereas the CM1 reduced such iron deposition. Thus, 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) can be considered a candidate bidentate oral iron chelator and is effective in the removal of toxic irons in blood compartment and tissues. The effectiveness and toxicity of the CM1 need to be investigated extensively in thalassemia mice and patients with iron overload.

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Removal of erythrocyte membrane iron in vivo ameliorates the pathobiology of murine thalassemia.

Cited by 38 publications

References 26 publications

βMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in β thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles

βMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in β thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles

Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme

Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice

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