ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.
ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.
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DOI：
10.1161/atvbaha.114.304017
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
van de Wetering K
中科院分区：
文献类型：
--
作者：
Jansen RS;Duijst S;Mahakena S;Sommer D;Szeri F;Váradi A;Plomp A;Bergen AA;Oude Elferink RP;Borst P;van de Wetering K
ABCC6 突变是异位矿化障碍弹力假黄瘤 (PXE) 和某些形式的婴儿期全身动脉钙化的基础，这两种疾病都会影响心血管系统。利用培养细胞，我们最近发现 ATP 结合盒亚家族 C 成员 6 (ABCC6) 介导 ATP 的细胞释放，ATP 在细胞外快速转化为 AMP 和矿化抑制剂无机焦磷酸盐 (PPi)。目前的研究旨在确定体内哪些组织以 ABCC6 依赖性方式释放 ATP，释放的 ATP 在何处转化为 AMP 和 PPi，以及人类 PXE 患者的血浆 PPi 浓度是否较低。使用培养的原代肝细胞和体内肝脏灌注实验，我们发现 ABCC6 介导肝脏中 ATP 的直接正弦释放。在肝细胞外，但仍在肝脉管系统内，释放的 ATP 转化为 AMP 和 PPi。 PXE 患者缺乏功能性 ABCC6 导致血浆 PPi 浓度大幅降低。肝脏 ABCC6 介导的 ATP 释放是循环 PR 的主要来源，揭示了肝脏在全身 PPi 稳态中意想不到的作用。 PXE 患者的血浆 PPi 水平显着降低，这解释了他们的矿化障碍。我们的结果表明，全身 PPi 相对稳定，PXE、婴儿期广泛动脉钙化和其他异位矿化障碍可以通过 PPi 补充疗法来治疗。
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. 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. Hepatic ABCC6-mediated ATP release is the main source of circulating PR, 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.