The role of PGE^sub 2^ in human atherosclerotic plaque on platelet EP^sub 3^ and EP^sub 4^ receptor activation and platelet function in whole blood

• Published in: Journal of thrombosis and thrombolysis 2011-08, Vol.32 (2), p.158
• Main Authors: Schober, Lisa J, Khandoga, Anna L, Dwivedi, Suman, Penz, Sandra M, Maruyama, Takayuki, Brandl, Richard, Siess, Wolfgang
• Format: Article
• Language: English
• ISSN: 0929-5305; 1573-742X
• DOI: 10.1007/s11239-011-0577-6

Atherosclerosis has an important inflammatory component. Macrophages accumulating in atherosclerotic arteries produce prostaglandin E^sub 2^ (PGE^sub 2^), a main inflammatory mediator. Platelets express inhibitory receptors (EP^sub 2^, EP^sub 4^) and a stimulatory receptor (EP^sub 3^) for this prostanoid. Recently, it has been reported in ApoE^sup -/-^ mice that PGE^sub 2^ accumulating in inflammatory atherosclerotic lesions might contribute to atherothrombosis after plaque rupture by activating platelet EP^sub 3^, and EP^sub 3^ blockade has been proposed to be a promising new approach in anti-thrombotic therapy. The aim of our investigation was to study the role of PGE^sub 2^ in human atherosclerotic plaques on human platelet function and thrombus formation. Plaque PGE^sub 2^ might either activate or inhibit platelets depending on stimulation of either EP^sub 3^ or EP^sub 4^, respectively. We found that the two EP^sub 3^-antagonists AE5-599 (300 nM) and AE3-240 (300 nM) specifically and completely inhibited the synergistic effect of the EP^sub 3^-agonist sulprostone on U46619-induced platelet aggregation in blood. However, these two EP^sub 3^-antagonists neither inhibited atherosclerotic plaque-induced platelet aggregation, GPIIb/IIIa exposure, dense and alpha granule secretion in blood nor reduced plaque-induced platelet thrombus formation under arterial flow. The EP^sub 4^-antagonist AE3-208 (1-3 μM) potentiated in combination with PGE^sub 2^ (1 μM) ADP-induced aggregation, demonstrating that PGE^sub 2^ enhances platelet aggregation when the inhibitory EP^sub 4^-receptor is inactivated. However, plaque-induced platelet aggregation was not augmented after platelet pre-treatment with AE3-208, indicating that plaque PGE^sub 2^ does not stimulate the EP^sub 4^-receptor. We found that PGE^sub 2^ was present in plaques only at very low levels (15 pg PGE^sub 2^/mg plaque). We conclude that PGE^sub 2^ in human atherosclerotic lesions does not modulate (i.e. stimulate or inhibit) atherothrombosis in blood after plaque rupture.[PUBLICATION ABSTRACT]