Myocardialinfarctiondamageshearttissuebothduringtheinitialischemiaandthesubsequentreperfusionoftissueswithoxygen.Corticosteroidscanprotectcardiactissuefromdamagefollowingaheartattack,butthemechanismsbywhichcorticosteroidsarecardioprotectivehavenotbeenclearandnegativesideeffectssuchasreducedwoundhealingmayresultfromtheiruse.Corticosteroidsexertavarietyofactionsthroughbindingtotheglucocorticoidreceptor(GR),amemberofthesteroidhormonereceptorgenefamily.GRactsasaligand-dependenttranscriptionfactor,butsomeofthecardioprotectiveeffectsmediatedbyGR-boundcorticosteroidsarenon-transcriptionalinnature.Glucocorticoidsarecommonlyusedasanti-inflammatorydrugsinavarietyofconditions,andsomeoftheireffectsintheheartresultfrominhibitionoftheinflammatoryresponseofhearttissuetoischemiaandreperfusion.NF-kBisatranscriptionfactorinvolvedinsignalingbyinflammatoryfactorssuchasTNF,andisrepressedbyglucocorticoids.Annexin-1isacalcium-dependentphospholipidbindingproteinwhoseexpressionisinducedbycorticosteroidsandinhibitstheinfiltrationofneutrophilsintotissue,blockingreperfusion-inducedinflammatoryheartdamage.Anon-transcriptionalcardioprotectiveeffectofglucocorticoidsisactivationofNOproductionbyendothelialnitricoxidesynthase(eNOS).GlucocorticoidsactivateeNOSthroughactivationofPI3kinaseandAKTandincreasedNOproducedbyeNOScandiffuseintosurroundingtissuestopreventclottingandcausevasodilation.Thebeta-2adrenergicreceptorcanalsoactivatePI3kinaseandmaysynergizewithglucocorticoidsinthispathway.Theatrialnatriureticfactor(ANF)isapeptidesecretedbytheatrialwallinresponsetoincreasedatrialpressuresuchasoccursduringcardiacfailureandtobedecreasedbymyocardialinfarction.GlucocorticoidsincreasethesecretionofANFbyactingatthetranscriptionalleveltoincreaseexpressionofthepro-ANFpeptide,perhapsinducingincreasedwaterexcretioninthekidneystoreducebloodvolumeandreduceatrialpressure.Theexplorationofglucorticoidresponsesmayallowtheidentificationofcompoundsthatretainthecardioprotectiveactivitiesbutdonotinhibitwoundhealing.AlternativemechanismsofeNOSactivationmayalsoprovidearoutetoidentifycardioprotectivedrugs.

Contributor:KosiGramatikoff,PhD

REFERENCES:SchmidtP,HolsboerF,SpenglerD.Beta(2)-adrenergicreceptorspotentiateglucocorticoidreceptortransactivationviaGproteinbetagamma-subunitsandthephosphoinositide3-kinasepathway.MolEndocrinol.2001Apr;15(4):553-64.SzaboC,ThiemermannC,WuCC,PerrettiM,VaneJR.Attenuationoftheinductionofnitricoxidesynthasebyendogenousglucocorticoidsaccountsforendotoxintoleranceinvivo.ProcNatlAcadSciUSA.1994Jan4;91(1):271-5.ThiemermannC.Corticosteroidsandcardioprotection.NatMed.2002May;8(5):453-5.Noabstractavailable.WuF,YanW,PanJ,MorserJ,WuQ.Processingofpro-atrialnatriureticpeptidebycorinincardiacmyocytes.JBiolChem.2002May10;277(19):16900-5.

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