氧化应激与糖尿病Oxidative stress and Diabetes费.ppt

OxidativeStressandDiabetes,JianLiBeijingInstituteofGeriatricsMinistryofHealth,Redoxrheostat“invascularcells,Reactiveoxygenspecies(=ROS),O2,O2-,H2O2,acidicpH,SuperoxydeDismutase(SOD),NADPHoxidase,Superoxideanion,Hydrogenperoxide,ProposedfunctionsofROS,killingofmicroorganismsDNAdamagecancerogenesisageingcelldeathNOinactivationandperoxynitritegeneration,regulationofcellgrowthanddifferentiationregulationofcellfunctionoxygensensingactivationofredox-sensitivetranscriptionfactorsactivationofredox-sensitivesecondmessengersystems,Whereandwhyarereactiveoxygenspeciesgenerated?,Mitochondriaby-productoftheoxidativemetabolismPhagocyteNADPHoxidasemicrobialkillingNADPHoxidaseofnon-phagocyticcellscellgrowth,cellsignaling,NOX-typeNADPHoxidasesassuperoxide-producingenzymes,TheNOXfamilyofNADPHoxidases,Review:Lambethetal.Novelhomologsofgp91phox.TrendsinBiochemicalSciences25:459-461,2000.,gp91phoxhomology,EF-hands,Nox1colonNox2phagocytesNox3innerearNox4kidney,Nox5testisandlymphoidtissues,O2,O2-,NADPH,e-,StructureoftheNAD(P)Hoxidase,CharacteristicsofneutrophilandvascularNAD(P)Hoxidase,NAD(P)HOxidaseActivation,Adenovirus-inducedoverexpressionofPKC-2causesthemembranoustranslocationofp47phoxandp67phox,AmodelillustratinghowincreasedROSproductioninaccumulatedfatcontributestometabolicsyndrome,MechanismforincreasedROSproductioninducedbydiabetesandinsulin-resistantstate,LinkingvariousriskfactorstoROSgenerationinthedevelopmentofIDDM,Initiationandamplificationoftheimmune/inflammatoryresponsebyROS-inducedNFBactivationin-celldeath,SchematicillustrationofROS-mediatedNFBactivation,ElevatedglucoseandFFAlevelscontributetothepathophysiologyofdiabetesviathegenerationofROS,Theroleofserinekinaseactivationinoxidativestressinducedinsulinresistance,Vasculareffectsofreactiveoxygenspecies(ROS),ModulationofcellularfunctionbyROSincardiovasculardiseases,PotentialroleofNADPHoxidaseinthepathogenesisofdiabeticnephropathy,EffectofhighglucoselevelandPMAonROSproductioninaorticsmoothmusclecells(A)andendothelialcells(B),EffectofdiphenyleneiodoniumonhighglucoseorPMA-inducedincreaseinROSproductioninaorticsmoothmusclecells(A)orendothelialcells(B),PKC-inhibitionsuppressesdiabetes-inducedO2-production,Redox-dependentsignalingpathwaysbyAngIIinvascularsmoothmusclecells,Detectionofintracellularproductionofreactiveoxygenspecies.A.FluorescencemicroscopyvisualizationofROSproductioninpericytesandsmoothmusclecells.a:control;b:cellsculturedin25mMglucoseandAGE-LysstimulatedwithAngII;candd:correspondingphasecontrastmicroscopy.B.Pericytesculturedinthepro-diabeticenvironment,wereloadedfor30minat37oCwith5mMDCF-DA.,Theeffectofhighglucoseconcentration,AGE-LysandtheircombinationwithAngIIonintracellularcalciumCa2+i,DetectionofO2-productionbydihydroethidiumstaininginmesangialcellsoverexpressingPKC-2,Superoxideproductioninnonatheroscleroticandatheroscleroticarteries,nonatheroscleroticarteriesatheroscleroticarteries,ExpressionofNAD(P)Hoxidasesubunitsinnonatheroscleroticandatheros