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Journal of Thrombosis and Thrombolysis

, Volume 32, Issue 2, pp 158–166 | Cite as

The role of PGE2 in human atherosclerotic plaque on platelet EP3 and EP4 receptor activation and platelet function in whole blood

  • Lisa J. Schober
  • Anna L. Khandoga
  • Suman Dwivedi
  • Sandra M. Penz
  • Takayuki Maruyama
  • Richard Brandl
  • Wolfgang SiessEmail author
Article

Abstract

Atherosclerosis has an important inflammatory component. Macrophages accumulating in atherosclerotic arteries produce prostaglandin E2 (PGE2), a main inflammatory mediator. Platelets express inhibitory receptors (EP2, EP4) and a stimulatory receptor (EP3) for this prostanoid. Recently, it has been reported in ApoE−/− mice that PGE2 accumulating in inflammatory atherosclerotic lesions might contribute to atherothrombosis after plaque rupture by activating platelet EP3, and EP3 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 PGE2 in human atherosclerotic plaques on human platelet function and thrombus formation. Plaque PGE2 might either activate or inhibit platelets depending on stimulation of either EP3 or EP4, respectively. We found that the two EP3-antagonists AE5-599 (300 nM) and AE3-240 (300 nM) specifically and completely inhibited the synergistic effect of the EP3-agonist sulprostone on U46619-induced platelet aggregation in blood. However, these two EP3-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 EP4-antagonist AE3-208 (1–3 μM) potentiated in combination with PGE2 (1 μM) ADP-induced aggregation, demonstrating that PGE2 enhances platelet aggregation when the inhibitory EP4-receptor is inactivated. However, plaque-induced platelet aggregation was not augmented after platelet pre-treatment with AE3-208, indicating that plaque PGE2 does not stimulate the EP4-receptor. We found that PGE2 was present in plaques only at very low levels (15 pg PGE2/mg plaque). We conclude that PGE2 in human atherosclerotic lesions does not modulate (i.e. stimulate or inhibit) atherothrombosis in blood after plaque rupture.

Keywords

Platelets Atherosclerotic plaque Thrombus Prostaglandin E2 EP3-receptor EP4-receptor 

Notes

Acknowledgements

The study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG Si 274/9), the August-Lenz-Stiftung, the University of Munich (Förderprogramm für Forschung und Lehre der LMU; Reg-No. 86/2008 to L.J.S.), the Bayern University (the Graduate Program of the “Bayerische Eliteförderungsgesetz BayEFG” to A.L.K.), and the Hella-Langer-Stiftung (S.M.P.). The technical assistance of Kathrin von Oheimb, Barbara Böhlig, Brigitte Zimmer und Diana Wagner is greatly appreciated. The results are part of the doctoral thesis of L.J.S. at the University of Munich.

Supplementary material

Supplementary material 1 (MPG 3970 kb)

Supplementary material 2 (MPG 9336 kb)

11239_2011_577_MOESM3_ESM.doc (24 kb)
Supplementary material 3 (DOC 24 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Lisa J. Schober
    • 1
  • Anna L. Khandoga
    • 1
  • Suman Dwivedi
    • 1
  • Sandra M. Penz
    • 1
  • Takayuki Maruyama
    • 2
  • Richard Brandl
    • 3
  • Wolfgang Siess
    • 1
    Email author
  1. 1.Institute for Prevention of Cardiovascular DiseasesLudwig Maximilians University of Munich MünchenGermany
  2. 2.Ono Pharmaceutical CoOsakaJapan
  3. 3.Department of Vascular SurgeryClinic SchwabingMunichGermany

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