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Prostaglandin E2 differentially modulates human platelet function through the prostanoid EP2 and EP3 receptors

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dc.contributor.author Petrucci G.
dc.contributor.author De Cristofaro R.
dc.contributor.author Rutella S.
dc.contributor.author Ranelletti F.O.
dc.contributor.author Pocaterra D.
dc.contributor.author Lancellotti S.
dc.contributor.author Habib A.
dc.contributor.author Patrono C.
dc.contributor.author Rocca B.
dc.contributor.editor
dc.date Feb-2011
dc.date.accessioned 2017-10-05T15:30:56Z
dc.date.available 2017-10-05T15:30:56Z
dc.date.issued 2011
dc.identifier 10.1124/jpet.110.174821
dc.identifier.isbn
dc.identifier.issn 00223565
dc.identifier.uri http://hdl.handle.net/10938/15284
dc.description.abstract Activated human platelets synthesize prostaglandin (PG) E2, although at lower rate than thromboxane A2. PGE2 acts through different receptors (EP1-4), but its role in human platelet function remains poorly characterized compared with thromboxane. We studied the effect of PGE2 and its analogs on in vitro human platelet function and platelet and megakaryocyte EP expression. Platelets preincubated with PGE 2 or its analogs were stimulated with agonists and studied by optical aggregometry. Intraplatelet calcium mobilization was investigated by the stopped flow method; platelet vasodilator-stimulated phosphoprotein (VASP), P-selectin, and microaggregates were investigated by flow cytometry. PGE 2 at nanomolar concentrations dose-dependently increased the slope (velocity) of the secondary phase of ADP-induced platelet aggregation (EC 50, 25.6 ± 6 nM; Emax of 100 ± 19percent increase versus vehicle-treated), without affecting final maximal aggregation. PGE 2 stabilized reversible aggregation induced by low ADP concentrations (EC50, 37.7 ± 9 nM). The EP3 agonists, 11-deoxy-16,16- dimethyl PGE2 (11d-16dm PGE2) and sulprostone enhanced the secondary wave of ADP-induced aggregation, with EC50 of 48.6 ± 10 nM (Emax, 252 ± 51percent) and 5 ± 2 nM (E max, 300 ± 35percent), respectively. The EP2 agonist butaprost inhibited ADP-induced secondary phase slopes (IC50, 40 ± 20 nM). EP4 stimulation had minor inhibitory effects. 11d-16dm PGE2 alone raised intraplatelet Ca2+ and enhanced ADP-induced Ca 2+ increase. 11d-16dm PGE2 and 17-phenyltrinor PGE 2 (EP3 andgt; EP1 agonist) at nanomolar concentrations counteracted PGE1-induced VASP phosphorylation and induced platelet microaggregates and P-selectin expression. EP1, EP2, EP3, and EP4 were expressed on human platelets and megakaryocytes. PGE2 through different EPs finely modulates human platelet responsiveness. These findings should inform the rational selection of novel antithrombotic strategies based on EP modulation. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.
dc.format.extent
dc.format.extent Pages: (391-402)
dc.language English
dc.publisher BETHESDA
dc.relation.ispartof Publication Name: Journal of Pharmacology and Experimental Therapeutics; Publication Year: 2011; Volume: 336; no. 2; Pages: (391-402);
dc.relation.ispartofseries
dc.relation.uri
dc.source Scopus
dc.subject.other
dc.title Prostaglandin E2 differentially modulates human platelet function through the prostanoid EP2 and EP3 receptors
dc.type Article
dc.contributor.affiliation Petrucci, G., Department of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy
dc.contributor.affiliation De Cristofaro, R., Department of Medicine, Catholic University School of Medicine, Rome, Italy
dc.contributor.affiliation Rutella, S., Department of Hematology, Catholic University School of Medicine, Rome, Italy, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Pisana, Rome, Italy
dc.contributor.affiliation Ranelletti, F.O., Department of Pathology, Catholic University School of Medicine, Rome, Italy
dc.contributor.affiliation Pocaterra, D., Department of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy
dc.contributor.affiliation Lancellotti, S., Department of Medicine, Catholic University School of Medicine, Rome, Italy
dc.contributor.affiliation Habib, A., Department of Biochemistry, American University of Beirut, Beirut, Lebanon
dc.contributor.affiliation Patrono, C., Department of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy
dc.contributor.affiliation Rocca, B., Department of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy
dc.contributor.authorAddress Rocca, B.; Department of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy; email: b.rocca@tiscali.it
dc.contributor.authorCorporate University: American University of Beirut Medical Center; Faculty: Faculty of Medicine; Department: Biochemistry and Molecular Genetics;
dc.contributor.authorDepartment Biochemistry and Molecular Genetics
dc.contributor.authorDivision
dc.contributor.authorEmail b.rocca@tiscali.it
dc.contributor.authorFaculty Faculty of Medicine
dc.contributor.authorInitials Petrucci, G
dc.contributor.authorInitials De Cristofaro, R
dc.contributor.authorInitials Rutella, S
dc.contributor.authorInitials Ranelletti, FO
dc.contributor.authorInitials Pocaterra, D
dc.contributor.authorInitials Lancellotti, S
dc.contributor.authorInitials Habib, A
dc.contributor.authorInitials Patrono, C
dc.contributor.authorInitials Rocca, B
dc.contributor.authorOrcidID
dc.contributor.authorReprintAddress Rocca, B (reprint author), Catholic Univ, Sch Med, Dept Pharmacol, Largo Francesco Vito 1, I-00168 Rome, Italy.
dc.contributor.authorResearcherID
dc.contributor.authorUniversity American University of Beirut Medical Center
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dc.description.citedCount 12
dc.description.citedTotWOSCount 11
dc.description.citedWOSCount 11
dc.format.extentCount 12
dc.identifier.articleNo
dc.identifier.coden JPETA
dc.identifier.pubmedID 21059804
dc.identifier.scopusID 78751555761
dc.identifier.url
dc.publisher.address 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA
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dc.relation.ispartofConferenceCode
dc.relation.ispartofConferenceDate
dc.relation.ispartofConferenceHosting
dc.relation.ispartofConferenceLoc
dc.relation.ispartofConferenceSponsor
dc.relation.ispartofConferenceTitle
dc.relation.ispartofFundingAgency
dc.relation.ispartOfISOAbbr J. Pharmacol. Exp. Ther.
dc.relation.ispartOfIssue 2
dc.relation.ispartOfPart
dc.relation.ispartofPubTitle Journal of Pharmacology and Experimental Therapeutics
dc.relation.ispartofPubTitleAbbr J. Pharmacol. Exp. Ther.
dc.relation.ispartOfSpecialIssue
dc.relation.ispartOfSuppl
dc.relation.ispartOfVolume 336
dc.source.ID WOS:000286309800012
dc.type.publication Journal
dc.subject.otherAuthKeyword
dc.subject.otherChemCAS 5 (4 chlorophenyl) 1 (4 methoxyphenyl) 3 trifluoromethyl 1h pyrazole, 188817-13-2
dc.subject.otherChemCAS 6 isopropoxy 9 oxo 2 xanthenecarboxylic acid, 33458-93-4
dc.subject.otherChemCAS acetylsalicylic acid, 493-53-8, 50-78-2, 53663-74-4, 53664-49-6, 63781-77-1
dc.subject.otherChemCAS butaprost, 69648-38-0
dc.subject.otherChemCAS indometacin, 53-86-1, 74252-25-8, 7681-54-1
dc.subject.otherChemCAS prostaglandin E2, 363-24-6
dc.subject.otherChemCAS sulprostone, 60325-46-4, 96420-78-9
dc.subject.otherChemCAS adenosine diphosphate, 20398-34-9, 58-64-0
dc.subject.otherChemCAS calcium, 14092-94-5, 7440-70-2
dc.subject.otherChemCAS collagen, 9007-34-5
dc.subject.otherChemCAS Adenosine Diphosphate, 58-64-0
dc.subject.otherChemCAS Aspirin, 50-78-2
dc.subject.otherChemCAS Calcium, 7440-70-2
dc.subject.otherChemCAS Cell Adhesion Molecules
dc.subject.otherChemCAS Collagen, 9007-34-5
dc.subject.otherChemCAS Dinoprostone, 363-24-6
dc.subject.otherChemCAS Microfilament Proteins
dc.subject.otherChemCAS P-Selectin
dc.subject.otherChemCAS PTGER2 protein, human
dc.subject.otherChemCAS PTGER3 protein, human
dc.subject.otherChemCAS Phosphoproteins
dc.subject.otherChemCAS Receptors, Prostaglandin E, EP2 Subtype
dc.subject.otherChemCAS Receptors, Prostaglandin E, EP3 Subtype
dc.subject.otherChemCAS vasodilator-stimulated phosphoprotein
dc.subject.otherIndex 11 deoxy 16,16 dimethylprostaglandin e2
dc.subject.otherIndex 17 phenyl trinor prostaglandin e2
dc.subject.otherIndex 5 (4 chlorophenyl) 1 (4 methoxyphenyl) 3 trifluoromethyl 1h pyrazole
dc.subject.otherIndex 6 isopropoxy 9 oxo 2 xanthenecarboxylic acid
dc.subject.otherIndex acetylsalicylic acid
dc.subject.otherIndex butaprost
dc.subject.otherIndex indometacin
dc.subject.otherIndex PADGEM protein
dc.subject.otherIndex prostaglandin E2
dc.subject.otherIndex prostanoid
dc.subject.otherIndex prostanoid receptor
dc.subject.otherIndex sulprostone
dc.subject.otherIndex unclassified drug
dc.subject.otherIndex vasodilator stimulated phosphoprotein
dc.subject.otherIndex actin binding protein
dc.subject.otherIndex adenosine diphosphate
dc.subject.otherIndex calcium
dc.subject.otherIndex cell adhesion molecule
dc.subject.otherIndex collagen
dc.subject.otherIndex PADGEM protein
dc.subject.otherIndex phosphoprotein
dc.subject.otherIndex prostaglandin E receptor 2
dc.subject.otherIndex prostaglandin E receptor 3
dc.subject.otherIndex prostaglandin E2
dc.subject.otherIndex PTGER2 protein, human
dc.subject.otherIndex PTGER3 protein, human
dc.subject.otherIndex vasodilator stimulated phosphoprotein
dc.subject.otherIndex vasodilator-stimulated phosphoprotein
dc.subject.otherIndex article
dc.subject.otherIndex calcium mobilization
dc.subject.otherIndex drug mechanism
dc.subject.otherIndex human
dc.subject.otherIndex human cell
dc.subject.otherIndex IC 50
dc.subject.otherIndex megakaryocyte
dc.subject.otherIndex priority journal
dc.subject.otherIndex protein expression
dc.subject.otherIndex protein phosphorylation
dc.subject.otherIndex protein protein interaction
dc.subject.otherIndex thrombocyte aggregation
dc.subject.otherIndex thrombocyte function
dc.subject.otherIndex blood
dc.subject.otherIndex dose response
dc.subject.otherIndex drug effect
dc.subject.otherIndex metabolism
dc.subject.otherIndex phosphorylation
dc.subject.otherIndex physiology
dc.subject.otherIndex thrombocyte
dc.subject.otherIndex Adenosine Diphosphate
dc.subject.otherIndex Aspirin
dc.subject.otherIndex Blood Platelets
dc.subject.otherIndex Calcium
dc.subject.otherIndex Cell Adhesion Molecules
dc.subject.otherIndex Collagen
dc.subject.otherIndex Dinoprostone
dc.subject.otherIndex Dose-Response Relationship, Drug
dc.subject.otherIndex Humans
dc.subject.otherIndex Microfilament Proteins
dc.subject.otherIndex P-Selectin
dc.subject.otherIndex Phosphoproteins
dc.subject.otherIndex Phosphorylation
dc.subject.otherIndex Platelet Aggregation
dc.subject.otherIndex Receptors, Prostaglandin E, EP2 Subtype
dc.subject.otherIndex Receptors, Prostaglandin E, EP3 Subtype
dc.subject.otherKeywordPlus ANTIPLATELET THERAPY
dc.subject.otherKeywordPlus CYCLIC-AMP
dc.subject.otherKeywordPlus AGGREGATION
dc.subject.otherKeywordPlus EXPRESSION
dc.subject.otherKeywordPlus SUBTYPES
dc.subject.otherKeywordPlus INHIBITION
dc.subject.otherKeywordPlus ISOFORMS
dc.subject.otherKeywordPlus ANALOGS
dc.subject.otherKeywordPlus ASPIRIN
dc.subject.otherKeywordPlus PGE(2)
dc.subject.otherWOS Pharmacology and Pharmacy


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