Details

Autor(en) / Beteiligte

• Schober, Lisa J.
• Khandoga, Anna L.
• Dwivedi, Suman
• Penz, Sandra M.
• Maruyama, Takayuki
• Brandl, Richard
• Siess, Wolfgang

Titel

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.