Iron Overload and Heart Fibrosis in Mice Deficient for Both β2-Microglobulin and Rag1

Santos, Manuela M.; Sousa, Maria de; Rademakers, L. H. P. M.; Marx, Jean L.; Schilham, Marco W.

doi:10.1016/s0002-9440(10)64827-4

Cited by 47 publications

(44 citation statements)

References 39 publications

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“…To our knowledge, this is the first demonstration of the impact of an HLA-A allele (HLA-A29) and a mutation in a non-classical MHC-class I gene located 4 Mb away (H63D) on lymphocyte numbers. The consistent finding of a phenotypic association between low lymphocyte numbers and high hepatic iron storage in HH patients (Porto et al 1997(Porto et al , 1998 and in lymphocyte-defective knockout mice (De Sousa et al 1994;Santos et al 1996Santos et al , 2000, led us to the present finding of significantly higher numbers of CD8 + T cells in HLA-A29 normal subjects carrying the H63D mutation. This observation may give us some insight into the mechanism whereby the lymphocytes could contribute to the regulation of iron metabolism.…”

Section: Discussionsupporting

confidence: 67%

“…Strong linkage disequilibrium between H63D and the HLA-A29 allele itself was confirmed. To address the question of the biological significance with regard to both our earlier work demonstrating a significant association between lymphocyte numbers and the phenotypic expression of iron overload in humans (reviewed in De Sousa et al 2000;Porto et al 1998Porto et al , 2001, and in experimental models of iron overload (De Sousa et al 1994;Levy et al 2000;Fleming et al 2001;Santos et al 2000;Sproule et al 2001;Ten-Elshof et al 1999), we examined lymphocyte subpopulations in normal subjects based on the presence or absence of the H63D mutation and the HLA-A29 allele. Significantly higher CD8 + T lymphocyte counts were observed in subjects simultaneously carrying the H63D and the HLA-A29 alleles.…”

Section: Introductionmentioning

confidence: 99%

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Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Cardoso¹,

Alves

Mascarenhas³

et al. 2002

Immunogenetics

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The major histocompatibility complex (MHC) shows a remarkable conservation of particular HLA antigens and haplotypes in linkage disequilibrium in most human populations, suggesting the existence of a convergent evolution. A recent example of such conservation is the association of particular HLA haplotypes with the HFE mutations. With the objective of exploring the significance of that association, the present paper offers an analysis of the linkage disequilibrium between HLA alleles or haplotypes and the HFE mutations in a Portuguese population. Allele and haplotype associations between HLA and HFE mutations were first reviewed in a population of 43 hemochromatosis families. The results confirmed the linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. In order to extend the study of the linkage disequilibrium between H63D and the HLA-A29-containing haplotypes in a normal, random population, an additional sample of 398 haplotypes was analyzed. The results reveal significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a co-selection of H63D and the HLA-A29 allele itself. An insight into the biological significance of this association is given by the finding of significantly higher CD8 + T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Cardoso¹,

Alves

Mascarenhas³

et al. 2002

Immunogenetics

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“…In some animal models of iron overload, the occurrence of both cardiac iron deposition and fibrosis have been reported. 17,18 Our data suggest that iron deposition may exacerbate the cardiac fibrosis induced by angiotensin II. The findings that the myocardial fibrosis that occurs after myocardial ischemia can be attenuated by angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist 19 and that less cardiac fibrosis is observed in the AT 1 receptor knockout mouse than in wild-type 20 suggest that angiotensin II has a crucial role in the development of cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 79%

Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

et al. 2002

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Background-Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. Methods and Results-Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. Conclusions-Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II.In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.

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“…Iron concentration in the cerebellum of 12-and 24-month-old Cp Ϫ/Ϫ and Cp ϩ/ϩ mice was measured by flame atomic absorption spectrometry (fAAS). Tissue samples were prepared according to a previously described protocol (Santos et al, 2000). Briefly, the whole cerebellum from individual animals was weighed wet and then dried for 20 h at 106°C, and the dry weight was measured.…”

Section: Methodsmentioning

confidence: 99%

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Jeong¹,

David²

2006

J. Neurosci.

133

145

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Iron is essential for a variety of cellular functions, but its levels and bioavailability must be tightly regulated because of its toxic redox activity. A number of transporters, binding proteins, reductases, and ferroxidases help maintain iron homeostasis to prevent cell damage. The multi-copper ferroxidase ceruloplasmin (Cp) converts toxic ferrous iron to its nontoxic ferric form and is required for iron efflux from cells. Absence of this enzyme in humans leads to iron accumulation and neurodegeneration in the CNS. Here we report on the changes that occur in the cerebellum of Cp null (Cp Ϫ/Ϫ ) mice with aging. We show that iron accumulation, which is reflected in increased ferritin expression, occurs mainly in astrocytes by 24 months in Cp Ϫ/Ϫ mice and is accompanied by a significant loss of these cells. In contrast, Purkinje neurons and the large neurons in the deep nuclei of Cp Ϫ/Ϫ mice do not accumulate iron but express high levels of the iron importer divalent metal transporter 1, suggesting that these cells may be iron deprived. This is also accompanied by a significant reduction in the number of Purkinje neurons. These data suggest that astrocytes play a central role in the acquisition of iron from the circulation and that two different mechanisms underlie the loss of astrocytes and neurons in Cp Ϫ/Ϫ mice. These findings provide a better understanding of the degenerative changes seen in humans with aceruloplasminemia and have implications for normal aging and neurodegenerative diseases in which iron accumulation occurs.

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Iron Overload and Heart Fibrosis in Mice Deficient for Both β2-Microglobulin and Rag1

Cited by 47 publications

References 39 publications

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

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