China-JapanCardiovascularForum2019NewStrategiesforImmune-mediatedHeartDiseasesMitsuakiIsobeDepartmentofCardiovascularMedicineTokyoMedicalandDentalUniversityImmune-mediatedheartdiseasesIschemia-reperfusioninjuryAtherosclerosisRestenosisCardiacallograftrejectionCardiacallograftvasculopathyMyocarditisCongestiveheartfailureArrhythmiaImmune-mediatedheartdiseasesIschemia-reperfusioninjuryAtherosclerosisRestenosisCardiacallograftrejectionCardiacallograftvasculopathyMyocarditisCongestiveheartfailureArrhythmiaInflammationincoronaryarteriosclerosisandatherogenesisPPARγ(Peroxisomeproliferator-activatedreceptor-γ)NFκBAcutecardiacallograftrejectionEctopichearttransplantionrecipients:C3H/Hedonors:BALB/cfullmismatchAdministrationofpioglitazone(3mg/kg/day)totherecipientmice.MurinehearttransplantationProlongationofheartgraftbypioglitazone1Survival

Rate0.80.60.4*Pioglitazone(3mg/kg/day)Controlchow0.2010203040506070*p<0.05PostoperativeDaysKosuge,Suzuki,Isobe:Circulation113:2613-2622、2019SuppressionofTcellProliferationbyPioglitazoneinMixedLymphocyteReaction*0.8**Optical

Density0.60.4*p<0.050.20R:responder(recipient)S:stimulator(donor)Pio:pioglitazoneChroniccardiacrejectionGraftarterialdisease(GAD)AcceleratedcoronarysclerosisGraftvasculopathyCardiacallograftvasculopathyMyocardiumRCASmallarteriesPathology:DiffuseintimalthickeningofsmalltolargecoronaryarteriesProgression:monthstoyearsRiskfactors:CMVinfectionepisodesofacuterejectionTherapy:?LAD8-y-oboyLCXChroniccardiacallograftrejectionCardiacallograftvasculopathyrecipients:C57BL/6donors:Bm12classIImismatch-10714212835424956daysControlchowPioglitazone(3mg/kg/day)Telmisartan(10mg/kg/day)sacrificeAttenuationofGraftArteriosclerosisbyTreatmentwithPioglitazoneorTelmisartanp<0.05ControlLuminal

occlusion

(%)TelmisartanControlPioglitazonep<0.05Pioglitazone8WeeksafterTransplantationControlTelmisartanKosuge,Suzuki,Isobe:Circulation2019SMCProliferationAssaySMCsAortaPioglitazonetelmisartanactivatedsplenocytesProliferationSuppressionofSMCproliferation?SuppressionofSMCProliferationafterInteractionwithSplenocytesbyPioglitazoneorTelmisartan*5.0**0.70.60.50.40.30.2***OpticalDensity4.03.02.01.000.10Summary1?PPARγisassociatedwithpathophysiologyofimmune-mediatedheartdiseases.?PPAR-γagonists(pioglitazoneandtelmisartan)areeffectiveinsuppressingexperimentalcardiacallograftrejection(acuterejectionandallograftvasculopathy).ReferencesKosuge,Suzuki,Isobe:Circulation113:2613-2622,2019Isobe,Kosuge,Suzuki:ATVB,26:1447-1456,2019Kosuge,Suzuki,Isobe:ATVB,26:2660-2665,2019Onai,Suzuki,Maejima:AmJPhysiol,292,H530-538,2019Kosuge,Suzuki,Isobe,Transplanation,inpressMaejima,Suzuki,Okada,Isobe:insubmissionInflammationincoronaryarteriosclerosisandatherogenesisPPARγ(Peroxisomeproliferator-activatedreceptor-γ)NFκBLPSTNFTCellTCRNFκBRoleofNF-kBinCardiovascularDiseasesStimuliAnoxiaReactiveoxygenspeciesLPSCytokines(IL-1β,TNFα)Re-oxygenationLipoproteinThrombinNF-κBActivationGeneExpressionCytokines(IL-1β,TNFα)iNOS,COX-2Adhesionmolecules(ICAM-1,VCAM-1)Immunoreceptors(MHCclassI,II)IL-6,M-CSF,GM-CSFChemokines(MCP-1,…)Acutephaseprotein(CRP,…)HeartfailureVascularremodelingAllograftrejectionMyocarditisReperfusioninjuryVentricularremodelingNF-κBdecoy-MechanismofAction-StimuliI-?BkinasesI-?BkinasesInflammatorymoleculesDegradationCellMembraneI-κBp50p65PI-κBp50p65I-κBXmRNANF-?Bp50p65p50p65DecoyDecoyNucleusp50p65XInflammatorygenesCis-ElementAcuteMyocarditisExperimentalAllergicMyocarditisinRatsImmunizationLewisratswereimmunizedwithporcinecardiacmyosin.InvivogenetransferInjectionofHVJ-liposome-NFκBdecoyatcoronarycuspFITC-labeledDecoyinRatHeartDay0,7or1421daysaftertransfectionNFkBdecoyreducesextentofautoimmunemyocariditisControl(%)1008060NFkBdecoy40200UTSDday0day7day14Myocarditis-affectedarea(injectionatday7)(YokosekiO,IsobeM,CircRes2019)MethodofgenetransfertocardiacallograftDonorHVJ-liposomeHVJ-DonorHeartDecoyTransfectionTransfection:10min,4CIschemictime:30minRecipient28daysHistologicalanalysisEffectofNFκBdecoyonGADEvGstainingPDGF-BmRNAVCAM-1ScrambledecoyNFκBdecoy(Suzuki,Isobe,GeneTherapy,2019)GeneTransferSystemDecoy+microbubblecomplexUltrasound(US)WireinjuryInhibitionofintimalhyperplasiabyNF-kBdecoytransfectionNeointimalformation(I/M)I/M2p<0.05NoUltrasound1*(-)(+)(+)(+)(-)(-)(+)(+)(-)(+)(-)(+)DecoyMicrobubbleUltrasoundUltrasoundEvG,Day14ClinicaltrialforpreventionofcoronaryrestenosisafterangioplastyJapanTrialtoPreventRestenosisAfterStentusingNFkBdecoyOligodeoxynucleotidesasGeneTherapy(J-PRAN)ThefirstclinicaltrialofgenetherapyforheartdiseaseinJapanCollaborationwithKyushuUniv,OsakaUniv,andTokyoMedandDentUniv.DecoytransfectionafterstentimplantationNovirusvectorDosetrialforsafetyEvaluationat6monthsbyangiographyandIVUSChannelBalloon(Remedy)NF-kBdecoy:case1(49-y-omale)Before2.5yearsafter#2:decoy#2:decoyDecember6,2019(Suzuki,Isobe,CircJ2019)May22,2019ResultsPatientID(dose)12I-001I-002(1mg）(1mg）genderMMage4475%QCABeforePCI%QCAAfterPCI%QCA6molater759000025345678910Q-001Q-002Q-004Q-005Q-007Q-009Q-012Q-013(1mg）(1mg）(1mg）(1mg）(2mg）(2mg）(2mg）(2mg）MMMFFMMM757847795857706690909099000045502555909090999990909000250000025476725502590251112131415161718I-003Q-017Q-018Q-019Q-022Q-028Q-032A-001(2mg）(2mg）(4mg）(4mg）(4mg）(4mg）(4mg）(4mg）MMMMMMMM565476665785-9975909900002525―*68.953(JGeneMed,inpress)SummaryofQCAPatientswithRestenosis(>75%byQCA)NegativePositivePatients171BeforePCIAfterPCIRates94.1%5.9%6Mo.LaterAverage%Restenosis（byQCA）%Restenosis88.51.539.6ConclusionsPPARγandNFκBaregoodmoleculartargetsfortreatmentofimmune-mediatedcardiovasculardiseases.Furtherstudiesshouldbeconductedtoexplorethepossibilitytodevelopnewtherapeuticstrategies.AcknowledgementTokyoMedicalandDentalUniversityJun-ichiSuzukiHisanoriKosugeNoritakaKogaNorikoTamuraMasahitoOgawaRyuichiMorishitaYasufumiKanedaKensukeEgashiraHiroshiItoOsakaUniversityKyushuUniversityAkitaUniversitySuppressionofCytokinesExpressioninAllograftsbyTreatmentwithPioglita