Genetics in Arterial Calcification

Rutsch, Frank; Nitschke, Yvonne; Terkeltaub, Robert

doi:10.1161/circresaha.111.247965

Cited by 160 publications

(109 citation statements)

References 176 publications

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“…The absence of NT5E results in ectopic mineralization owing to reduced extracellular formation of adenosine, which leads to increased expression of tissue- nonspecific alkaline phosphatase (TNAP), a PPi-degrading enzyme (36). Based on the similarities in ACDC, GACI, and PXE, others have hypothesized that ABCC6 prevents PXE through a mechanism overlapping the ENPP1-NT5E pathway (37,38). Our findings provide direct experimental support for this hypothesis and position ABCC6 immediately upstream of the ENPP1-NT5E pathway.…”

supporting

confidence: 66%

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Jansen

Küçükosmanoğlu

Haas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

235

310

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Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATPbinding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6 −/− mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE has remained a mystery. Here we report that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium from HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyze the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data are demonstrated in Abcc6 −/− mice, which had plasma PPi levels <40% of those found in WT mice. This study provides insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an asyet unidentified but ABCC6-dependent mechanism.ATP secretion | ectopic calcification | MRP6 | ENPP1

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supporting

confidence: 66%

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Jansen

Küçükosmanoğlu

Haas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

235

310

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“…In rodents, warfarin treatment induces rapid VC and decreased arterial compliance (5,6) akin to elastocalcinosis, a condition prevalent in the elderly population and characterized by calcium deposition along the elastic lamellae. Extensive research over the past decades has established that VC is at least in part a cell-mediated process that includes stimulation of osteogenic/chondrogenic differentiation in vascular smooth muscle (7,8), vesicle release, apoptosis, extracellular matrix degradation, and loss of calcification inhibitors (9,10).…”

Section: Vascular Calcification (Vc)mentioning

confidence: 99%

Quercetin Attenuates Warfarin-induced Vascular Calcification in Vitro Independently from Matrix Gla Protein

Beazley

Eghtesad

Nurminskaya

2013

Journal of Biological Chemistry

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Background: Molecular mechanism(s) of warfarin-induced vascular calcification are not well known. Results: Inhibition of ␤-catenin signaling with shRNA or quercetin prevents osteoblastic transformation and calcification in VSMCs and calcification in aortic rings treated with warfarin, independent from MGP and protein carboxylation. Conclusion: Quercetin inhibits vascular calcification via ␤-catenin signaling. Significance: Quercetin may be instrumental in treatment of warfarin-induced vascular calcification.

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“…It was recently reported that some cases of GACI are due to ABCC6 mutations and show characteristic PXE clinical manifestations [10,11]. In addition, deficiency in CD73 (encoded by the NT5E gene) causes a human disease called arterial calcifications due to deficiency in CD73 (ACDC), which is characterized by a spontaneous and premature onset of arterial calcification, closely related but phenotypically different from GACI and PXE [12]. Finally, mutations in the mouse ABCC6 gene have been associated with dystrophic cardiac calcification (DCC), a disease characterized by hydroxyapatite deposition in necrotic myocytes [13,14].…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of gene expression in ABCC6 knockdown HepG2 cells

Miglionico¹,

Armentano²,

Carmosino³

et al. 2014

Cellular and Molecular Biology Letters

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ABCC6 protein is an ATP-dependent transporter that is mainly found in the basolateral plasma membrane of hepatocytes. ABCC6 deficiency is the primary cause of several forms of ectopic mineralization syndrome. Mutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by ectopic calcification of the elastic fibers in dermal, ocular and vascular tissues. Mutations in the mouse ABCC6 gene were also associated with dystrophic cardiac calcification. Reduced levels of ABCC6 protein were found in a β-thalassemic mouse model. Moreover, some cases of generalized arterial calcification in infancy are due to ABCC6 mutations. In order to study the role of ABCC6 in the pathogenesis of ectopic mineralization, the expressions of genes involved in this process were evaluated in HepG2 cells upon stable knockdown of ABCC6 by small hairpin RNA (shRNA) technology. ABCC6 knockdown in HepG2 cells causes a significant upregulation of the genes promoting mineralization, such as TNAP, and a parallel downregulation of genes with anti-mineralization activity, such as NT5E, Fetuin A and Osteopontin. Although the absence of ABCC6 has been already associated with ectopic mineralization syndromes, this study is the first to show a direct relationship between reduced ABCC6 levels and the expression of pro-mineralization genes in hepatocytes.

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Genetics in Arterial Calcification

Cited by 160 publications

References 176 publications

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Quercetin Attenuates Warfarin-induced Vascular Calcification in Vitro Independently from Matrix Gla Protein

Dysregulation of gene expression in ABCC6 knockdown HepG2 cells

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