PGE2 decreases reactivity of human platelets by activating EP2 and EP4

Smith, James P.; Haddad, Elias V.; Downey, Jason D.; Breyer, Richard M.; Boutaud, Olivier

doi:10.1016/j.thromres.2010.04.003

Cited by 46 publications

(66 citation statements)

References 31 publications

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“…118 EP 3 is highly expressed in platelets and is involved in platelet activation 119 ; EP 3 null mice displayed increased bleeding times and were less prone to developing thromboembolisms. 120 PGE 2 acting on EP 2 and EP 4 reduces human platelet hyper-reactivity, which is associated with increased cardiovascular risk, 121 and was shown to inhibit mouse platelet aggregation. 122 PGE 2 also contributes to dyslipidemia and insulin resistance.…”

Section: Pge 2 In Other Aspects Of the Metabolic Syndromementioning

confidence: 99%

PGE2, Kidney Disease, and Cardiovascular Risk

Nasrallah

Hassouneh

Hébert

2016

Journal of the American Society of Nephrology

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An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE 2 in these events. This review summarizes the role of PGE 2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE 2 signaling in hypertension and diabetes, and outlines the contribution of PGE 2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE 2 could lead to new avenues to improve therapeutic options and disease management strategies. 27: 666-676, 201627: 666-676, . doi: 10.1681 Accelerated cardiovascular disease is the leading cause of mortality in patients with kidney disease. 1,2 This implies that kidney disease has a major effect on global cardiovascular risk, affecting fluid (volume, BP), electrolyte, and acid base balance, among many other cardiovascular risk factors. In fact, renal transplantation ameliorates cardiovascular risk, improves quality of life, and reduces mortality. 2 PGs are important homeostatic regulators of kidney function. PGE 2 is the major product of cyclooxygenase (COX)-2 and microsomal PGE synthase 1 (mPGES1), and both of these enzymes are elevated in renal diseases. [3][4][5][6][7][8][9][10] PGE 2 binds four EP receptors (EP 1-4 ) to activate G protein signaling responses. Figure 1 illustrates the COX pathway leading to PGE 2 , as well as its target receptors. These receptors are often coexpressed in cells and usually have opposing effects (protective and harmful). PGE 2 acting on EP can alter vascular tone and influence renal blood flow and hemodynamics. 11-15 PGE 2 also stimulates the macula densa to activate the renin-angiotensin-aldosterone system, a key mediator of kidney injury. [16][17][18][19] Inflammatory, immune, and oxidative stress responses are influenced by PGE 2 , which are reported to alter growth, fibrosis, and apoptosis in renal cells. 20-26 PGE 2 also contributes to disturbances in collecting duct salt and water transport in polyuric diseases, 19,[27][28][29] and b cell defects in sodium and potassium handling associated with type I distal renal tubule acidosis. 30 PGE 2 /EP 4 also compensates for the loss of vasopressin V2 receptors in mouse diabetes insipidus. 28 Although attempts to block PGE 2 using COX-2 or mPGES1 inhibitors have failed, selective inhibition of EP receptors may prove to be quite useful in controlling the deleterious effects of COX-2/mPGES1/PGE 2 , while leaving the protective responses intact. EP 1 mediates many of the pathologic effects of PGE 2 in kidne...

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Section: Pge 2 In Other Aspects Of the Metabolic Syndromementioning

confidence: 99%

PGE2, Kidney Disease, and Cardiovascular Risk

Nasrallah

Hassouneh

Hébert

2016

Journal of the American Society of Nephrology

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“…1). Recent studies have shown that platelet function is regulated via several prostanoid receptors expressed in platelets, including EP 2 (Kuriyama et al, 2010;Smith et al, 2010), EP 3 (Fabre et al, 2001;Ma et al, 2001), EP 4 (Iyú et al, 2010;Kuriyama et al, 2010;Philipose et al, 2010;Smith et al, 2010), IP (Murata et al, 1997), and TP (Thomas et al, 1998). Among these receptors, EP 2 and EP 4 , in addition to IP, mediate inhibitory signaling in platelets.…”

Section: Discussionmentioning

confidence: 99%

The Novel Prostaglandin I₂Mimetic ONO-1301 Escapes Desensitization in an Antiplatelet Effect Due to Its Inhibitory Action on Thromboxane A₂Synthesis in Mice

Kashiwagi

Yuhki

Kojima

et al. 2015

J Pharmacol Exp Ther

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ONO-1301 [(E)-[5-[2-[1-phenyl-1-(3-pyridyl)methylidene-aminooxy]ethyl]-7,8-dihydronaphthalene-1-yloxy]acetic acid] is a novel prostaglandin (PG) I 2 mimetic with inhibitory activity on the thromboxane (TX) A 2 synthase. Interestingly, ONO-1301 retains its inhibitory effect on platelet aggregation after repeated administration, while beraprost, a representative agonist for the PGI 2 receptor (IP), loses its inhibitory effect after repeated administration. In the present study, we intended to clarify the mechanism by which ONO-1301 escapes desensitization of an antiplatelet effect. In platelets prepared from wild-type mice, ONO-1301 inhibited collagen-induced aggregation and stimulated cAMP production in an IP-dependent manner. In addition, ONO-1301 inhibited arachidonic acid-induced TXA 2 production in platelets lacking IP. Despite the decrease in stimulatory action on cAMP production, the antiplatelet effect of ONO-1301 hardly changed after repeated administration for 10 days in wild-type mice. Noteworthy, beraprost could retain its antiplatelet effect after repeated administration in combination with a low dose of ozagrel, a TXA 2 synthase inhibitor. Therefore, we hypothesized that chronic IP stimulation by beraprost induces an increase in TXA 2 production, leading to reduction in the antiplatelet effect. As expected, repeated administration of beraprost increased the plasma and urinary levels of a TXA 2 metabolite, while ONO-1301 did not increase them significantly. In addition, beraprost could retain the ability to inhibit platelet aggregation after repeated administration in mice lacking the TXA 2 receptor (TP). These results indicate that TP-mediated signaling participates in platelet desensitization against IP agonists and that simultaneous inhibition of TXA 2 production confers resistance against desensitization on IP agonists.

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“…Thus, and as opposed to the action of EP3, EP2 and EP4 activation inhibit platelet aggregation [13] . However, the relative importance of this effect is unclear both in mice [13][14][15] and humans [13,14,[16][17][18][19][20] . Murine observations revealed that the impact of PGE2 on thrombosis, i.e.…”

Section: The Platelet Ep3 Paradigm In Micementioning

confidence: 99%

“…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%

“…Indeed, for unclear reasons, the potentiating effect of PGE2 is detected in PRP using light scattering earlier after stimulation than in whole blood using impedancemetry [22] . Lastly, interindividual variations observed in the effect of PGE2 on human platelets [19,32] can also be better understood by considering the variable initial amounts of cAMP in platelets rather than the variable innate ability of platelets to respond [25] . Thus, the reinterpretation of inconsistent data with these analytical tools, potentiation window and initial cAMP levels, reveals that PGE2 indeed potentiates the effect of agonists on human platelets in whole blood.…”

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

confidence: 99%

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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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PGE2 decreases reactivity of human platelets by activating EP2 and EP4

Cited by 46 publications

References 31 publications

PGE2, Kidney Disease, and Cardiovascular Risk

PGE2, Kidney Disease, and Cardiovascular Risk

The Novel Prostaglandin I₂Mimetic ONO-1301 Escapes Desensitization in an Antiplatelet Effect Due to Its Inhibitory Action on Thromboxane A₂Synthesis in Mice

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

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PGE2 decreases reactivity of human platelets by activating EP2 and EP4

Cited by 46 publications

References 31 publications

PGE2, Kidney Disease, and Cardiovascular Risk

PGE2, Kidney Disease, and Cardiovascular Risk

The Novel Prostaglandin I2Mimetic ONO-1301 Escapes Desensitization in an Antiplatelet Effect Due to Its Inhibitory Action on Thromboxane A2Synthesis in Mice

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

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The Novel Prostaglandin I₂Mimetic ONO-1301 Escapes Desensitization in an Antiplatelet Effect Due to Its Inhibitory Action on Thromboxane A₂Synthesis in Mice