title: PGE2 decreases reactivity of human platelets by activating EP2 and EP4.
abstract: BACKGROUND
  Platelet hyperreactivity associates with cardiovascular events in humans. Studies in mice and humans suggest that prostaglandin E2 (PGE2) regulates platelet activation. In mice, activation of the PGE2 receptor subtype 3 (EP3) promotes thrombosis, but the significance of EP3 in humans is less well understood.
  
  
  OBJECTIVE
  To characterize the regulation of thromboxane-dependent human platelet activation by PGE2.
  
  
  METHODS
  Platelets collected from nineteen healthy adults were studied using an agonist of the thromboxane receptor (U46,619), PGE2, and selective agonists and/or antagonists of the EP receptor subtypes. Platelet activation was assayed by (1) optical aggregometry, (2) measurement of dense granule release, and (3) single-platelet counting.
  
  
  RESULTS
  Healthy volunteers demonstrated significant interindividual variation in platelet response to PGE2. PGE2 completely inhibited U46,619-induced platelet aggregation and ATP release in 26% of subjects; the remaining 74% had partial or no response to PGE2. Antagonism of EP4 abolished the inhibitory effect of PGE2. In all volunteers, a selective EP2 agonist inhibited U46,619-induced aggregation. Furthermore, the selective EP3 antagonist DG-041 converted all PGE2 nonresponders to full responders.
  
  
  CONCLUSIONS
  There is significant interindividual variation of platelet response to PGE2 in humans. The balance between EP2, EP3, and EP4 activation determines its net effect. PGE2 can prevent thromboxane-induced platelet aggregation in an EP4-dependent manner. EP3 antagonism converts platelets of nonresponders to a PGE2-responsive phenotype. These data suggest that therapeutic targeting of EP pathways may have cardiovascular benefit by decreasing platelet reactivity.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Smith
authors.forename: Elias V
authors.initials: EV
authors.lastname: Haddad
authors.forename: Jason D
authors.initials: JD
authors.lastname: Downey
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Olivier
authors.initials: O
authors.lastname: Boutaud
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology*; D030501:Epididymal Secretory Proteins; D005260:Female; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D023083:beta-Defensins
chemical_list: C426184:DEFB126 protein, human; D030501:Epididymal Secretory Proteins; D023083:beta-Defensins; D015232:Dinoprostone
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