Cardiovascular involvement in thalassaemic patients with Pseudoxanthoma elasticum‐like skin lesions: a long‐term follow‐up study

Cianciulli, Paolo; Sorrentino, Francesco; Maffei, Laura; Amadori, Sergio; Cappabianca, Maria Pia; Foglietta, E.; Carnevali, Elena; Pasquali‐Ronchetti, I.

doi:10.1046/j.1365-2362.2002.01032.x

Cited by 34 publications

(41 citation statements)

References 26 publications

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“…Because PXE-like mineralization in ␤-thalassemia patients arise independently of ABCC6 mutations 16 and is clinically and structurally identical to inherited PXE, [17][18][19][20] the calcification of elastic fibers is very likely a phenocopy of inherited PXE. Therefore, we hypothesized that a converging molecular mechanism independent of genetic mutations alters the expression of ABCC6 or disrupts the biologic properties of its product in the liver and/or kidneys as a secondary consequence of the hemoglobinopathy.…”

Section: 15mentioning

confidence: 99%

A Mouse Model of β-Thalassemia Shows a Liver-Specific Down-Regulation of Abcc6 Expression

Martin

Douet

VanWart

et al. 2011

The American Journal of Pathology

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␤-Thalassemia and pseudoxanthoma elasticum (PXE) are distinct genetic disorders. Yet, a dystrophic mineralization phenotype similar to PXE has frequently been associated with ␤-thalassemia or sickle cell anemia patients of Mediterranean descent. These calcifications are clinically and structurally identical to inherited PXE. As we previously excluded the presence of PXE-causing mutations in the ABCC6 gene of ␤-thalassemia patients with PXE manifestations, we hypothesized that a molecular mechanism independent of gene mutations either altered the ABCC6 gene expression or disrupted the biologic properties of its product in the liver or kidneys, which are the tissues with the highest levels of expression. To test this possibility, we investigated Abcc6 synthesis in the liver and kidneys of a ␤-thalassemia mouse model (Hbb th3/؉ ). We found a progressive liver-specific down-regulation of the Abcc6 gene expression and protein levels by quantitative PCR, Western blotting, and immunofluorescence. The levels of Abcc6 protein decreased significantly at 6 months of age and stabilized at 10 months and older ages at ϳ25% of the wild-type protein levels. We studied the transcriptional regulation of the Abcc6 gene in wild-type and Hbb th3/؉ mice, and we identified the erythroid transcription factor NF-E2 as the main cause of the transcriptional down-regulation using transcription factor arrays and chromatin immunoprecipitation. The Hbb th3/؉ mice did not develop spontaneous calcification as seen in the Abcc6 ؊/؊ mice probably because the Abcc6 protein decrease occurred late in life and was probably insufficient to promote mineralization in the Hbb th3/؉ mouse C57BL/6J genetic background. Nevertheless, our result suggested that a similar decrease of ABCC6 expression occurs in the liver of ␤-thalassemia patients and may be responsible for their frequent PXE-like manifestations.

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Section: 15mentioning

confidence: 99%

A Mouse Model of β-Thalassemia Shows a Liver-Specific Down-Regulation of Abcc6 Expression

Martin

Douet

VanWart

et al. 2011

The American Journal of Pathology

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“…The characteristic cutaneous manifestation is yellowish papules resembling "plucked-chicken skin" distributed over neck, axillae, antecubital fossae, popliteal and groin areas. 3 The long-term follow-up study showed that PXE-like lesions were unrelated to severity of anemia, duration of blood transfusion, splenectomy and chelation history. 2,3 The differences among these two entities are demonstrated in Table 1.…”

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confidence: 99%

“…The cardiovascular manifestations include myocardial/intestinal infarction, intermittent claudication and transient ischemic attack, which result from arterial calcification. 3,4 Moreover, vascular aneurysm leads to gastrointestinal and intracranial hemorrhage. The characteristic cutaneous manifestation is yellowish papules resembling "plucked-chicken skin" distributed over neck, axillae, antecubital fossae, popliteal and groin areas.…”

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confidence: 99%

Pseudoxanthoma elasticum‐like lesions in beta‐thalassemia/hemoglobin E patient: A case report

Kasemsarn

Boonchai

2013

The Journal of Dermatology

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“…The genetic basis for these diseases cannot be directly linked to any structural or regulatory components involved in elastic fiber production (30,33,34). However, it has been suggested that the accumulation of iron in these patients, resulting from hemolysis, increased iron absorption, and multiple blood transfusions may lead to acquired elastic tissue defects (30).…”

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confidence: 99%

Fluctuations of Intracellular Iron Modulate Elastin Production

Bunda

Kaviani

Hinek

2005

Journal of Biological Chemistry

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Production of insoluble elastin, the major component of elastic fibers, can be modulated by numerous intrinsic and exogenous factors. Because patients with hemolytic disorders characterized with fluctuations in iron concentration demonstrate defective elastic fibers, we speculated that iron might also modulate elastogenesis. In the present report we demonstrate that treatment of cultured human skin fibroblasts with low concentration of iron 2-20 M (ferric ammonium citrate) induced a significant increase in the synthesis of tropoelastin and deposition of insoluble elastin. Northern blot and realtime reverse transcription-PCR analysis revealed that treatment with 20 M iron led to an increase of ϳ3-fold in elastin mRNA levels. Because treatment with an intracellular iron chelator, desferrioxamine, caused a significant decrease in elastin mRNA level and consequent inhibition of elastin deposition, we conclude that iron facilitates elastin gene expression. Our experimental evidence also demonstrates the existence of an opposite effect, in which higher, but not cytotoxic concentrations of iron (100 -400 M) induced the production of intracellular reactive oxygen species that coincided with a significant decrease in elastin message stability and the disappearance of iron-dependent stimulatory effect on elastogenesis. This stimulatory elastogenic effect was reversed, however, in cultures simultaneously treated with high iron concentration (200 M) and the intracellular hydroxyl radical scavenger, dimethylthiourea. Thus, presented data, for the first time, demonstrate the existence of two opposite iron-dependent mechanisms that may affect the steady state of elastin message. We speculate that extreme fluctuations in intracellular iron levels result in impaired elastic fiber production as observed in hemolytic diseases.Mature elastic fibers and laminae provide extensibility and elastic recoil to vascular walls and ligaments and form a connective tissue framework of lungs, elastic cartilage, and skin (1, 2). They are complex structures made of polymeric (insoluble) elastin and 12-nm microfibrils that consist of several glycoproteins, e.g. fibrillins, fibulins, and microfibril-associated glycoproteins (3-6). Elastic fiber formation (elastogenesis) is a complex process involving several intracellular and extracellular events. Cells (fibroblasts, endothelial cells, chondroblasts, or vascular smooth muscle cells) must first synthesize and secrete numerous glycoproteins to form a microfibrillar scaffold upon which tropoelastin, the precursor peptides, are properly assembled and covalently cross-linked by lysyl oxidase into a resilient polymer, insoluble elastin (7-10). Production of elastin reaches its highest levels in the third trimester of the fetal life and steadily decreases during early postnatal development (11,12). In undisturbed tissues, elastic fibers may last over the entire human lifespan (13,14).The net deposition of elastin appears to be controlled on both the transcriptional level (tropoelastin mRNA message express...

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Cardiovascular involvement in thalassaemic patients with Pseudoxanthoma elasticum‐like skin lesions: a long‐term follow‐up study

Cited by 34 publications

References 26 publications

A Mouse Model of β-Thalassemia Shows a Liver-Specific Down-Regulation of Abcc6 Expression

A Mouse Model of β-Thalassemia Shows a Liver-Specific Down-Regulation of Abcc6 Expression

Pseudoxanthoma elasticum‐like lesions in beta‐thalassemia/hemoglobin E patient: A case report

Fluctuations of Intracellular Iron Modulate Elastin Production

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