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OxidativeStressandDiabetesJianLiBeijingInstituteofGeriatricsMinistryofHealth

Redox"rheostat“invascularcells

Reactiveoxygenspecies

(=ROS)O2O2-H2O2acidicpH,SuperoxydeDismutase(SOD)NADPHoxidaseSuperoxideanionHydrogenperoxideProposedfunctionsofROSkillingofmicroorganismsDNAdamagecancerogenesisageingcelldeathNOinactivationandperoxynitritegenerationregulationofcellgrowthanddifferentiationregulationofcellfunctionoxygensensingactivationofredox-sensitivetranscriptionfactorsactivationofredox-sensitivesecondmessengersystemsWhereandwhyarereactiveoxygenspeciesgenerated?Mitochondriaby-productoftheoxidativemetabolismPhagocyteNADPHoxidasemicrobialkillingNADPHoxidaseofnon-phagocyticcells

cellgrowth,cellsignalingNOX-typeNADPHoxidases

assuperoxide-producingenzymes

FeFeoutsideinsideIVIIVIIIIIVNH2HHHHHHNADPHFADCOOHH115O2O2-e-TheNOXfamilyofNADPHoxidasesReview:Lambethetal.Novelhomologsofgp91phox.TrendsinBiochemicalSciences25:459-461,2000.gp91phoxhomologyEF-handsNox1 colonNox2 phagocytesNox3 innerearNox4 kidneyNox5testisandlymphoidtissuesO2O2-NADPHe-StructureoftheNAD(P)HoxidaseCharacteristicsofneutrophilandvascularNAD(P)HoxidaseNAD(P)HOxidaseActivationAdenovirus-inducedoverexpressionofPKC-β2causesthemembranoustranslocationofp47phoxandp67phoxAmodelillustratinghowincreasedROSproductioninaccumulatedfatcontributestometabolicsyndrome

MechanismforincreasedROSproductioninducedbydiabetesandinsulin-resistantstateLinkingvariousriskfactorstoROSgenerationinthedevelopmentofIDDM

Initiationandamplificationoftheimmune/inflammatoryresponsebyROS-inducedNFκBactivationinβ-celldeath

SchematicillustrationofROS-mediatedNFκBactivation

ElevatedglucoseandFFAlevelscontributetothepathophysiologyofdiabetesviathegenerationofROSTheroleofserinekinaseactivationinoxidativestressinducedinsulinresistanceVasculareffectsofreactiveoxygenspecies(ROS)ModulationofcellularfunctionbyROSincardiovasculardiseasesPotentialroleofNADPHoxidaseinthepathogenesisofdiabeticnephropathyEffectofhighglucoselevelandPMAonROSproductioninaorticsmoothmusclecells(A)andendothelialcells(B)Effectofdiphenyleneiodoniumonhighglucose–orPMA-inducedincreaseinROSproductioninaorticsmoothmusclecells(A)orendothelialcells(B)PKC-β

inhibitionsuppressesdiabetes-inducedO2-production

Redox-dependentsignalingpathwaysbyAngIIinvascularsmoothmusclecellsDetectionofintracellularproductionofreactiveoxygenspecies.A.FluorescencemicroscopyvisualizationofROSproductioninpericytesandsmoothmusclecells.a:control;b:cellsculturedin25mMglucoseandAGE-LysstimulatedwithAngII;candd:correspondingphasecontrastmicroscopy.B.Pericytesculturedinthepro-diabeticenvironment,wereloadedfor30minat37oCwith5mMDCF-DA.Theeffectofhighglucoseconcentration,AGE-LysandtheircombinationwithAngIIonintracellularcalcium[Ca2+]iDetectionofO2-

productionbydihydroethidiumstaininginmesangialcellsoverexpressingPKC-β2Superoxideproductioninnonatheroscleroticandatheroscleroticarteries

nonatheroscleroticarteriesatheroscleroticarteriesExpressionofNAD(P)Hoxidasesubunitsinnonatheroscl

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