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 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 human EA.hy926 endothelial cell line and primary human umbilical vein endothelial cells (HUVEC) we show that selective H1R activation increases intracellular NAADP levels and that H1R-induced calcium release involves both acidic organelles and endoplasmic
reticulum.
To assess that NAADP links H1R to Ca2+-signalling we used both microinjection of self-inactivating concentrations of NAADP and the specific NAADP receptor antagonist, Ned-19, both of which completely abolished H1R- 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 two-pore channels NAADP receptors, while thrombin-induced vWF secretion failed to be affected.
These findings demonstrate a novel and specific Ca2+-signalling mechanism activated through H1R in human endothelial cells revealing an obligatory role of NAADP in the control of vWF
secretion.
Authors
NAADP links histamine H1 receptors to secretion of von Willebrand factor in human endothelial cells
1. Bianca Esposito (1),
2. Guido Gambara (1),
3. Alexander M. Lewis (2),
4. Fioretta Palombi (1),
5. Alessio D'Alessio (1),
6. Lewis X. Taylor (2),
7. Armando A. Genazzani (3),
8. Elio Ziparo (1),
9. Antony Galione (2),
10. Grant C. Churchill (2), and
11. Antonio Filippini (1)
Author Affiliations
(1) Istituto Pasteur-Fondazione Cenci Bolognetti, D.A.H.F.M.O. Section of Histology & Medical Embryology, SAPIENZA University of
Rome, Rome, Italy;
(2) Dept. of Pharmacology, University of Oxford, Oxford, United Kingdom;
(3) DiSCAFF and DFB Center, Universita del Piemonte Orientale, Novara, Italy
Source
Blood
(MDN)
|