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

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