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1、SecretoryProductsFromEpicardialAdiposeTissueofPatientsWithType2DiabetesMellitusInduceCardiomyocyteDysfunctionSabrinaGreulich,PhD;BujarMaxhera,MD,PhD;GuyVandenplasMD;DaniellaHerzfelddeWiza;KonstantinosSmiris,MD;HeidiMueller;JessicaHeinrichs,MSc;MarcelB
2、lumensatt,MSc;ClaudeCuvelier,MD,PhD;PayamAkhyari,MD,PhD;JohannesB.Ruige,MD,PhD;D.MargrietOuwens,PhD*;JuergenEckel,PhD*Background—Secretedfactorsfromepicardialadiposetissue(EAT)havebeenimplicatedinthedevelopmentofcardiomyocytedysfunction.Thisstudyaimed
3、toassesswhetheralterationsinthesecretoryprofileofEATinpatientswithtype2diabetesmellitus(DM2)affectcontractilefunctionandinsulinactionincardiomyocytes.MethodsandResults—Contractilefunctionandinsulinactionwereanalyzedinprimaryadultratcardiomyocytesincub
4、atedwithconditionedmedia(CM)generatedfromexplantsofEATbiopsiesobtainedfrompatientswithoutandwithDM2.CMfromsubcutaneousandpericardialadiposetissuebiopsiesfromthesamepatientsservedasthecontrol.2CardiomyocytestreatedwithCM(EAT)fromDM2patientsshowedreduc
5、tionsinsarcomereshortening,cytosolicCafluxes,expressionofsarcoplasmicendoplasmicreticulumATPase2a,anddecreasedinsulin-mediatedAkt-Ser473-phosphorylationascomparedwithCMfromtheothergroups.ProfilingoftheCMshowedthatactivinA,angiopoietin-2,andCD14selecti
6、velyaccumulatedinCM-EAT-DM2versusCM-EATinpatientswithoutDM2andCMfromtheotherfatdepots.Accordingly,EATbiopsiesfromDM2patientswerecharacterizedbyclustersofCD14-positivemonocytes.Furthermore,SMAD2-phosphorylation,adownstreamtargetofactivinAsignaling,wase
7、levatedincardiomyocytestreatedwithCM(EAT)fromDM2patients,andthedetrimentaleffectsofCM(EAT)fromDM2patientswerepartiallyabolishedincardiomyocytespretreatedwithaneutralizingantibodyagainstactivinA.Downloadedfromhttp://ahajournals.orgbyonAugust12,2018Fina
8、lly,bothrecombinantactivinAandangiopoietin-2reducedcardiomyocytecontractilefunction,butonlyactivinAreducedtheexpressionofsarcoplasmicendoplasmicreticulumATPase2a.Conclusions—Collectively,ourdataimplicateDM2-relatedalterationsinthesecretoryprof
