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, functionally 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 H1Rinduced 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 thrombininduced 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)

NAADP links histamine H1 receptors to secretion of vonWillebrand factor in human endothelial cells / Esposito, Bianca; Gambara, Guido; Alexander M., Lewis; Palombi, Fioretta; Alessio, D’Alessio; Lewis X., Taylor; Armando A., Genazzani; Ziparo, Elio; Antony, Galione; Grant C., Churchill; Filippini, Antonio. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 117:18(2011), pp. 4968-4977. [10.1182/blood-2010-02-266338]

NAADP links histamine H1 receptors to secretion of vonWillebrand factor in human endothelial cells

ESPOSITO, BIANCA;GAMBARA, Guido;PALOMBI, Fioretta;ZIPARO, Elio;FILIPPINI, Antonio
2011

Abstract

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, functionally 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 H1Rinduced 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 thrombininduced 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)
2011
Istamina; Endotelio; Infiammazione
01 Pubblicazione su rivista::01a Articolo in rivista
NAADP links histamine H1 receptors to secretion of vonWillebrand factor in human endothelial cells / Esposito, Bianca; Gambara, Guido; Alexander M., Lewis; Palombi, Fioretta; Alessio, D’Alessio; Lewis X., Taylor; Armando A., Genazzani; Ziparo, Elio; Antony, Galione; Grant C., Churchill; Filippini, Antonio. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 117:18(2011), pp. 4968-4977. [10.1182/blood-2010-02-266338]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/381334
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