NAADP links histamine H1 receptors to secretion of von Willebrand factor in human endothelial cells
NAADP links histamine H1 receptors to secretion of von Willebrand factor in human endothelial cells
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DOI：
10.1182/blood-2010-02-266338
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发表时间：
2011-05-05
期刊：
影响因子：
20.3
通讯作者：
Filippini, Antonio
中科院分区：
文献类型：
--
作者：
Esposito, Bianca;Gambara, Guido;Filippini, Antonio
多种内皮激动剂诱导的反应是由细胞内Ca 2+的升高介导的，这表明不同的Ca 2+签名可以微调特定的炎症和血栓形成活动。为了寻找调节内皮效应器功能的新的细胞内机制，我们鉴定了烟酸腺嘌呤二核苷酸磷酸（NAADP）作为组胺通过H1受体（H1 R）诱导的Ca 2+释放的关键第二信使。NAADP是一种有效的细胞内信使，从溶酶体样酸性区室中动员Ca 2+，功能上与内质网偶联。使用人EA.hy926内皮细胞系和原代人脐静脉内皮细胞，我们表明，选择性H1 R激活增加细胞内NAADP水平和H1 R诱导的钙释放涉及酸性细胞器和内质网。为了评估NAADP将H1 R与Ca 2+信号传导联系起来，我们使用了微量注射自失活浓度的NAADP和特异性NAADP受体拮抗剂Ned-19，两者都完全消除了H1 R诱导的Ca 2+动员，但没有凝血酶诱导的Ca 2+动员。有趣的是，H1 R介导的血管性血友病因子（VWF）的分泌完全抑制治疗与Ned-19和siRNA敲低2孔通道NAADP受体，而凝血酶诱导的VWF分泌没有受到影响。这些研究结果表明，一种新的和特定的Ca 2+信号转导机制激活通过H1 R在人内皮细胞，这揭示了一个强制性的作用NAADP在控制VWF分泌。（血。2011;117（18）：4968-4977）
A variety of endothelial agonist-induced responses are mediated by rises in intracellular Ca2+, suggesting that different Ca2+ signatures could fine-tune specific inflammatory and thrombotic activities. In search of new intracellular mechanisms modulating endothelial effector functions, we identified nicotinic acid adenine dinucleotide phosphate (NAADP) as a crucial second messenger in histamine- induced Ca2+ release via H1 receptors (H1R). NAADP is a potent intracellular messenger mobilizing Ca2+ from lysosome-like acidic compartments, func-tionally coupled to the endoplasmic reticulum. Using the human EA.hy926 endothelial cell line and primary human umbilical vein endothelial cells, we show that selective H1R activation increases intracellular NAADP levels and that H1R-induced calcium release involves both acidic organelles and the endoplasmic reticulum. To assess that NAADP links H1R to Ca2+-signaling we used both microinjection of self-inactivating concentrations of NAADP and the specific NAADP receptor antagonist, Ned-19, both of which completely abolished H1R-induced but not thrombin-induced Ca2+ mobilization. Interestingly, H1R-mediated von Willebrand factor (VWF) secretion was completely inhibited by treatment with Ned-19 and by siRNA knockdown of 2-pore channel NAADP receptors, whereas thrombin-induced VWF secretion failed to be affected. These findings demonstrate a novel and specific Ca2+-signaling mechanism activated through H1R in human endothelial cells, which reveals an obligatory role of NAADP in the control of VWF secretion. (Blood. 2011;117(18):4968-4977)