The EP3-agonist sulprostone, but not prosta glandin E2 potentiates platelet aggregation in human blood

Schober, Lisa J; Khandoga, Anna L.; Penz, Sandra; Siess, Wolfgang

doi:10.1160/th09-12-0815

Cited by 11 publications

(8 citation statements)

References 19 publications

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“…1). We and others reported previously that sulprostone, a selective EP 3 -agonist, does not activate platelets on its own, but shows a potentiation of platelet aggregation induced by various agonists, such as U46619, collagen and ADP [18,[24][25][26]. We found that both EP 3 -antagonists showed a concentration-dependent inhibitory effect of the sulprostone-dependent potentiation of U46619-induced aggregation, which was significant for all concentrations tested (25-300 nM).…”

Section: Resultssupporting

confidence: 61%

“…PGE 2 was then measured by a specific enzyme immunoassay. Values are mean of duplicate determinations of one experiment influence platelet function in human blood [25]. Another difference of murine and human platelets has been observed recently by Kuriyama et al, who found a much higher inhibitory potency of a selective EP 4 -receptor-agonist in human platelets as compared to murine platelets [16].…”

Section: Discussionmentioning

confidence: 78%

“…The biphasic effect is apparently more pronounced in mice platelets [13,14,16,17], whereas studies with human platelets show less consistent results [26,29,32,33]. Our recent investigation of the effect of PGE 2 on platelets in human blood clearly showed no potentiation of platelet aggregation by low PGE 2 concentrations, and only a slight inhibition at high concentrations (5 lM) [25]. We conclude that in contrast to a selective EP 3 -agonist and to experiments done with murine platelets, PGE 2 with different concentrations has no significant effect on human platelets.…”

Section: Discussionmentioning

confidence: 89%

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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

Schober

Khandoga

Dwivedi

et al. 2011

J Thromb Thrombolysis

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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.

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Section: Resultssupporting

confidence: 61%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 89%

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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

Schober

Khandoga

Dwivedi

et al. 2011

J Thromb Thrombolysis

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“…However, even at an early time-point (1 min), we could not detect any permissive effect of EP3 stimulation on thrombus formation in whole blood under flow, which is in sharp contrast to ADP-induced adhesion of washed platelets to fibrinogen, where EP3 stimulation significantly accentuated the response. Moreover, it was reported that platelet aggregation in response to collagen was indeed augmented by sulprostone in whole blood aggregometry [18,31] . Although we cannot offer a conclusive explanation for this apparent contradiction at present, it might be hypothesized that collagen fully activates platelets in whole blood, which is further accentuated under high flow conditions.…”

Section: Discussionmentioning

confidence: 99%

The EP3 Agonist Sulprostone Enhances Platelet Adhesion But Not Thrombus Formation Under Flow Conditions

Pasterk

Philipose²,

Eller³

et al. 2015

Pharmacology

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Platelets express the EP2, EP3 and EP4 receptors. Prostaglandin (PG) E₂ has a biphasic effect on platelets. Low concentrations of PGE₂ enhance platelet aggregation through the activation of the EP3 receptors, while at high concentrations it attenuates aggregation via the EP4 receptor. Consequently, EP3 receptor inhibition was shown to inhibit artherothrombosis, but had no influence on bleeding time in vivo. In this study, we investigated the role of the EP3 receptor in adhesion and thrombus formation under flow conditions in vitro. The EP3 agonist sulprostone caused an increase in the adhesion of washed platelets to fibrinogen as well as to collagen under low shear stress, an effect that was blocked by the EP3 antagonist L-798106. In contrast, when whole blood was perfused over collagen-coated surfaces, sulprostone did not enhance binding and thrombus formation of platelets on collagen; at high concentrations it even attenuated this response. We conclude that in more physiological models of thrombus formation, the role for EP3 receptors is limited, indirectly suggesting that the primary action of PGE₂ in haemostasis might be an inhibitory one.

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“…These similarities suggest that murine data on atherothrombosis could be transferable to humans. However, a number of publications [9,19,[29][30][31][32] questioned this translation. In short, they showed that the effect of PGE2 on human platelets is restricted to inhibition, is dependent on the nature of the agonist, is variable amongst individuals or even is restricted to an in vitro feature.…”

Section: Does the Platelet Ep3 Paradigm Apply To Human Platelets?mentioning

confidence: 99%

Blocking the receptor EP3 to PGE2 as a way to safely prevent atherothrombosis

2016

Receptors Clin Investig

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Aspirin inhibits the platelet production of thromboxane A2 and its beneficial effect on myocardial infarction was demonstrated more than two decades ago. This result validated the strategy aimed at targeting platelet function to prevent myocardial infarction. Since then, numerous drugs targeting various activators of platelets have been developed to further improve prevention. However, the beneficial effect of all these drugs on atherothrombosis is limited by an increased risk of bleeding, because they target thrombosis effectors which are also key players in hemostasis. Since aspirin blocks the generation of numerous prostanoids, including inhibitors of platelet activation, targeting one of them might allow the antithrombotic activity to be maintained without promoting bleeding. In examining the roles of various arachidonic acid metabolites on atherothrombosis, we studied the prostaglandin E2 (PGE2). In vivo, PGE2 facilitates the responses of platelets to all their various activators through its receptor EP3. PGE2 is produced in relatively high amounts in the context of chronic inflammation such as atherosclerosis, and aggravates murine atherothrombosis. Conversely, PGE2 is not involved in hemostasis. As expected, blocking EP3 strikingly reduced atherothrombosis in mice without impacting bleeding tests. In a recent paper published in Prostaglandins & Other Lipid Mediators, we reviewed literature data about the effect of PGE2 and its receptor EP3 on platelet thrombosis and hemostasis in mice and humans. We concluded that cumulated data now justifies validating the role of EP3 blockers with phase III trials to safely improve the prevention of myocardial infarction.

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The EP3-agonist sulprostone, but not prosta glandin E2 potentiates platelet aggregation in human blood

Cited by 11 publications

References 19 publications

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

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

The EP3 Agonist Sulprostone Enhances Platelet Adhesion But Not Thrombus Formation Under Flow Conditions

Blocking the receptor EP3 to PGE2 as a way to safely prevent atherothrombosis

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