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Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1985-9. doi: 10.1161/ATVBAHA.114.304017. Epub 2014 Jun 26.

ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.

Author information

1
From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
2
From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.). k.vd.wetering@nki.nl.

Abstract

OBJECTIVE:

Mutations in ABCC6 underlie the ectopic mineralization disorder pseudoxanthoma elasticum (PXE) and some forms of generalized arterial calcification of infancy, both of which affect the cardiovascular system. Using cultured cells, we recently showed that ATP-binding cassette subfamily C member 6 (ABCC6) mediates the cellular release of ATP, which is extracellularly rapidly converted into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi). The current study was performed to determine which tissues release ATP in an ABCC6-dependent manner in vivo, where released ATP is converted into AMP and PPi, and whether human PXE ptients have low plasma PPi concentrations.

APPROACH AND RESULTS:

Using cultured primary hepatocytes and in vivo liver perfusion experiments, we found that ABCC6 mediates the direct, sinusoidal, release of ATP from the liver. Outside hepatocytes, but still within the liver vasculature, released ATP is converted into AMP and PPi. The absence of functional ABCC6 in patients with PXE leads to strongly reduced plasma PPi concentrations.

CONCLUSIONS:

Hepatic ABCC6-mediated ATP release is the main source of circulating PPi, revealing an unanticipated role of the liver in systemic PPi homeostasis. Patients with PXE have a strongly reduced plasma PPi level, explaining their mineralization disorder. Our results indicate that systemic PPi is relatively stable and that PXE, generalized arterial calcification of infancy, and other ectopic mineralization disorders could be treated with PPi supplementation therapy.

KEYWORDS:

multidrug resistance-associated proteins; nucleotides; pathologic calcification; pyrophosphatases; vascular calcification

Comment in

PMID:
24969777
DOI:
10.1161/ATVBAHA.114.304017
[Indexed for MEDLINE]
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