Cardiomyocyte ultrastructural damage in β‐thalassaemic mice

Sanyear, Chanita; Butthep, Punnee; Nithipongvanich, Ramaneeya; Sirankapracha, Pornpan; Winichagoon, Pranee; Fucharoen, Suthat; Svasti, Saovaros

doi:10.1111/iep.12044

Cited by 5 publications

(8 citation statements)

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“…[37][38][39] Also, these mice also had increased heart weight and cardiac iron levels even at the basal condition when compared with normal mice. 37,39 However, the study by Stoyanova et al was the only one not to observe increased cardiac iron accumulation in homozygous (Hbb d3(th) / Hbb d3(th) ) b-thalassemic mice. 38 This discrepancy could be due to the fact that Stoyanova et al used only Prussian blue staining to determine cardiac iron accumulation, which is a less sensitive method than the atomic absorption and colorimetric methods used by other studies.…”

Section: The Hearts Of B-thalassemic Micementioning

confidence: 99%

“…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%

“…The other models of β-thalassemic mice, homozygous (Hbb th1 /Hbb th1 ), (Hbb d3(th) /Hbb d3(th) ) and heterozygous β IVSII-654 , display a greater severity of the condition than the heterozygous (Hbb th-3 /Hbb + ) model does. 37–39 These mice showed decreased levels of RBC, Hb, Hct and impaired cardiac function indicated by decreased SV, EF, and FS. 37–39 Also, these mice also had increased heart weight and cardiac iron levels even at the basal condition when compared with normal mice.…”

Section: The Hearts Of β-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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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: The Hearts Of B-thalassemic Micementioning

confidence: 99%

Section: The Hearts Of B-thalassemic Micementioning

confidence: 99%

Section: The Hearts Of β-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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“…In addition to mouse models of β thalassemia, which is the secondary iron overload condition more closely linked to cardiac iron overload [ 63 ], animal models involving ablation of genes that are inactivated in hereditary hemochromatosis also represent useful and validated models of body (and heart) iron overload. Mouse models involving HFE [ 64 ], hemojuvelin [ 32 , 65 ], hepcidin [ 66 ], and transferrin receptor 2 (TfR2) [ 64 ] inactivation lead to iron loading phenotypes ranging from mild to severe.…”

Section: Preclinical Animal Models Of Cardiac Iron Overloadmentioning

confidence: 99%

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

Gammella

Recalcati

Rybińska

et al. 2015

Oxidative Medicine and Cellular Longevity

125

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The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies.

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“…Tail DNA was used to verify the genotype of each mouse. The phenotype of hemizygous ␤ IVSII-654 mice was categorized as ␤-thalassemic intermedia with iron deposition in the heart and liver, and imbalanced globin synthesis with ␣-to-␤-globin ratio of 1.26 (19,24,26). The homozygous ␤ IVSII-654 genotype is lethal, and the fetus usually dies in utero.…”

Section: Animalsmentioning

confidence: 99%

Bone microstructural defects and osteopenia in hemizygous β^IVSII-654knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function

Thongchote

Svasti

Teerapornpuntakit

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Thongchote K, Svasti S, Teerapornpuntakit J, Suntornsaratoon P, Krishnamra N, Charoenphandhu N. Bone microstructural defects and osteopenia in hemizygous ␤ IVSII-654 knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function. Am J Physiol Endocrinol Metab 309: E936 -E948, 2015. First published October 20, 2015 doi:10.1152/ajpendo.00329.2015.-␤-Thalassemia, a hereditary anemic disorder, is often associated with skeletal complications that can be found in both males and females. The present study aimed to investigate the age-and sex-dependent changes in bone mineral density (BMD) and trabecular microstructure in ␤ IVSII-654 knockin thalassemic mice. Dual-energy X-ray absorptiometry and computer-assisted bone histomorphometry were employed to investigate temporal changes in BMD and histomorphometric parameters in male and female mice of a ␤ IVSII-654 knockin mouse model of human ␤-thalassemia, in which impaired splicing of ␤-globin transcript was caused by hemizygous C¡T mutation at nucleotide 654 of intron 2. Young, growing ␤ IVSII-654 mice (1 mo old) manifested shorter bone length and lower BMD than their wild-type littermates, indicating possible growth retardation and osteopenia, the latter of which persisted until 8 mo of age (adult mice). Interestingly, two-way analysis of variance suggested an interaction between sex and ␤ IVSII-654 genotype, i.e., more severe osteopenia in adult female mice. Bone histomorphometry further suggested that low trabecular bone volume in male ␤ IVSII-654 mice, particularly during a growing period (1-2 mo), was primarily due to suppression of bone formation, whereas both a low bone formation rate and a marked increase in osteoclast surface were observed in female ␤ IVSII-654 mice. In conclusion, osteopenia and trabecular microstructural defects were present in both male and female ␤ IVSII-654 knockin thalassemic mice, but the severity, disease progression, and cellular mechanism differed between the sexes. ␤-thalassemia; bone histomorphometry; bone mineral density; osteoporosis ABERRANT SPLICING of ␤-globin messenger ribonucleic acid (mRNA) can lead to a hereditary autosomal recessive anemia known as ␤-thalassemia, which exhibits infantile onset of microcytic anemia, ineffective erythropoiesis, iron overload with iron deposition in solid organs, and bone marrow expansion (34). In several geographical regions, such as Southeast Asia and China, aberrant ␤-globin mRNA splicing caused by hemizygous C¡T mutation at nucleotide 654 of intron 2 (i.e., ϩ/␤ ) results in thalassemia intermedia, a mild-tomoderate form of ␤-thalassemia (6,16,19). ␤-Thalassemia not only impairs intramedullary erythropoiesis but is also associated with trabecular bone defect; however, the underlying mechanisms and detailed microstructural changes are not completely understood (14).To investigate the pathogenesis of ␤-thalassemia-associated sequelae, a transgenic mouse model subjected to human ␤ sequence knockin was used in the present study. Our recent preliminary study in sexually...

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Cardiomyocyte ultrastructural damage in β‐thalassaemic mice

Cited by 5 publications

References 22 publications

Cardiac complications in beta-thalassemia: From mice to men

Cardiac complications in beta-thalassemia: From mice to men

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

Bone microstructural defects and osteopenia in hemizygous β^IVSII-654knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function

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Cardiomyocyte ultrastructural damage in β‐thalassaemic mice

Cited by 5 publications

References 22 publications

Cardiac complications in beta-thalassemia: From mice to men

Cardiac complications in beta-thalassemia: From mice to men

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

Bone microstructural defects and osteopenia in hemizygous βIVSII-654knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function

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Bone microstructural defects and osteopenia in hemizygous β^IVSII-654knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function