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

Robert S. Jansen, Suzanne Duijst, Sunny Mahakena, Daniela Sommer, Flóra Szeri, András Váradi, Astrid Plomp, Arthur A. Bergen, Ronald P.J. Oude Elferink, Piet Borst, Koen Van De Wetering

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129 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1985-1989
Number of pages5
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number9
DOIs
Publication statusPublished - Sep 2014

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Jansen, R. S., Duijst, S., Mahakena, S., Sommer, D., Szeri, F., Váradi, A., Plomp, A., Bergen, A. A., Oude Elferink, R. P. J., Borst, P., & Van De Wetering, K. (2014). ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation - Brief report. Arteriosclerosis, thrombosis, and vascular biology, 34(9), 1985-1989. https://doi.org/10.1161/ATVBAHA.114.304017