Activation of Haem-Oxidized Soluble Guanylyl Cyclase with BAY 60-2770 in Human Platelets Lead to Overstimulation of the Cyclic GMP Signaling Pathway 英文参考文献.docVIP

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Activation of Haem-Oxidized Soluble Guanylyl Cyclase with BAY 60-2770 in Human Platelets Lead to Overstimulation of the Cyclic GMP Signaling Pathway 英文参考文献.doc

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Activation of Haem-Oxidized Soluble Guanylyl Cyclase with BAY 60-2770 in Human Platelets Lead to Overstimulation of the Cyclic GMP Signaling Pathway 英文参考文献

ActivationofHaem-OxidizedSolubleGuanylylCyclase withBAY60-2770inHumanPlateletsLeadto OverstimulationoftheCyclicGMPSignalingPathway CamilaB.Mendes-Silverio,LuizO.S.Leiria,RafaelP.Morganti,GabrielF.Anhe?,SisiMarcondes, Fab?′olaZ.Mo′nica,GilbertoDeNucci,EdsonAntunes* DepartmentofPharmacology,FacultyofMedicalSciences,UniversityofCampinas(UNICAMP),Sa?o Paulo,Brazil Abstract Background and Aims: Nitric oxide-independent soluble guanylyl cyclase (sGC) activators reactivate the haem-oxidized enzyme in vascular diseases. This study was undertaken to investigate the anti-platelet mechanisms of the haem- independentsGCactivatorBAY60-2770inhumanwashedplatelets.ThehypothesisthatsGCoxidationpotentiatestheanti- plateletactivitiesofBAY60-2770hasbeentested. Methods:Humanwashedplateletaggregationandadhesionassays,aswellasflowcytometryforaIIbb3integrinactivation and Western blot for a1 and b1 sGC subunits were performed. Intracellular calcium levels were monitored in platelets loadedwithafluorogeniccalcium-bindingdye(FluoForte). Results:BAY60-2770(0.001–10mM)producedsignificantinhibitionofcollagen(2mg/ml)-andthrombin(0.1U/ml)-induced plateletaggregationthatwasmarkedlypotentiatedbythesGCinhibitorODQ(10 mM).Infibrinogen-coatedplates,BAY60- 2770significantlyinhibitedplateletadhesion,aneffectpotentiatedbyODQ.BAY60-2770increasedthecGMPlevelsand 2+ reduced the intracellular Ca levels, both of which were potentiated by ODQ. The cell-permeable cGMP analogue 8-Br- cGMP (100mM) inhibited platelet aggregation and Ca2+ levels in an ODQ-insensitive manner. The cAMP levels remained unchangedbyBAY60-2770.Collagen-andthrombin-induceda b activationwasmarkedlyinhibitedbyBAY60-2770that IIb 3 wasfurtherinhibitedbyODQ.Theeffectsofsodiumnitroprusside(3mM)wereallpreventedbyODQ.IncubationwithODQ (10mM)significantlyreducedtheproteinlevelsofa1andb1sGCsubunits,whichwerepreventedbyBAY60-2770. Conclusion:TheinhibitoryeffectsofBAY60-2770onaggregation,adhesion,intracellularCa2+levelsandaIIbb3activatio