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The role of PGE2 in human atherosclerotic plaque on platelet EP3 and EP4 receptor activation and platelet function in whole blood
Ist Teil von
Journal of thrombosis and thrombolysis, 2011-08, Vol.32 (2), p.158-166
Ort / Verlag
Boston: Springer US
Erscheinungsjahr
2011
Quelle
SpringerLink (Online service)
Beschreibungen/Notizen
Atherosclerosis has an important inflammatory component. Macrophages accumulating in atherosclerotic arteries produce prostaglandin E
2
(PGE
2
), a main inflammatory mediator. Platelets express inhibitory receptors (EP
2
, EP
4
) and a stimulatory receptor (EP
3
) for this prostanoid. Recently, it has been reported in ApoE
−/−
mice that PGE
2
accumulating in inflammatory atherosclerotic lesions might contribute to atherothrombosis after plaque rupture by activating platelet EP
3
, and EP
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
2
in human atherosclerotic plaques on human platelet function and thrombus formation. Plaque PGE
2
might either activate or inhibit platelets depending on stimulation of either EP
3
or EP
4
, respectively. We found that the two EP
3
-antagonists AE5-599 (300 nM) and AE3-240 (300 nM) specifically and completely inhibited the synergistic effect of the EP
3
-agonist sulprostone on U46619-induced platelet aggregation in blood. However, these two EP
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
4
-antagonist AE3-208 (1–3 μM) potentiated in combination with PGE
2
(1 μM) ADP-induced aggregation, demonstrating that PGE
2
enhances platelet aggregation when the inhibitory EP
4
-receptor is inactivated. However, plaque-induced platelet aggregation was not augmented after platelet pre-treatment with AE3-208, indicating that plaque PGE
2
does not stimulate the EP
4
-receptor. We found that PGE
2
was present in plaques only at very low levels (15 pg PGE
2
/mg plaque). We conclude that PGE
2
in human atherosclerotic lesions does not modulate (i.e. stimulate or inhibit) atherothrombosis in blood after plaque rupture.