通过葡萄糖诱导氧化应激刺激血管内皮细胞中的nadph氧化酶4活性和表达的增加

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1、IncreasedactivityandexpressionofNADPHoxidase4stimulatedbyglucoseinducesoxidativestressinvascularendothelialcellsJianLIKeyLaboratoryofGeriatrics,BeijingInstituteofGeriatrics,MinistryofHealth,Beijing100730,Chinaβ-cellliverobesityβ-CellDysfunctionInsulinResistanceFFAVLDLF

2、FAVLDLGlucoseOxidativestressHypothesisRedox"rheostat“incellsWherearereactiveoxygenspeciesgenerated?Mitochondrialrespirtion-chainenzymecomplexxanthineoxidase,NOS,lipoxygenasePhagocyteNADPHoxidaseNADPHoxidaseofnon-phagocyticcells＊NADPHoxidaseisamajorsourceofvascularROSpr

3、oduction.NOX-typeNADPHoxidasesassuperoxide-producingenzymesFeFeoutsideinsideIVIIVIIIIIVNH2HHHHHHNADPHFADCOOHH115O2O2-e-StructureoftheNADPHoxidaseTheNOXfamilyofNADPHoxidasesgp91phoxhomologyEF-handsNox1colonNox2phagocytesNox3innerearNox4kidneyandvascularcellsNox5testisa

4、ndlymphoidtissuesO2O2-NADPHe-ABCDDPI:NOXinhibitor;Rotenone:inhibitorofmitochondrialrespirtion-chainenzymecomplex;L-NAME:NOSinhibitor;Oxypurinol:xanthineoxidaseinhibitorNADPHoxidaseisamajorsourceofvascularROSproductioninducedbyglucoseA:negativecontrol;B:HUVEC;C:20mMgluc

5、osetreatedHUVEC;D:positivecontrolGlucoseinducesapoptosisofHUVECAGCCGCGC:HUVEC;G:20mMglucose-treatedHUVECWesternblotGlucoseup-regulatestheexpressionofNOX4β-actinNOX4NOX2p22phoxp47phoxp67phoxRac1MAN1N2N3N4p22p47p67Rac1RT-PCR0102030glucose(mM)A:negativecontrol;B:transfect

6、edwithGFP-pcDNA3.1;C:transfectedwithNOX4-pcDNA3.1Over-expressionofNOX4increasesthelevelofROSandresultsinapoptosisABCABCABCABCNOX4-siRNAdecreasestheexpressionofNOX4andthelevelROSinHUVECCC+GS-FAMS-FAM+GS-NOX4S-NOX4+GCS-FAMS-NOX4******MechanismforincreasedROSproductionind

7、ucedbydiabetesandinsulin-resistantstateDiabetesHighglucoselevelInsulinresistanceObesityElevatedNEFAlevelDenovoDAGsynthesisVascularcellsPKCactivationNADPHoxidaseactivationSuperoxideROSActivationofNADPHoxidaseImmunoflurescencestainingofp47phoxPKC/p47phoxregulatestheactiv

8、ationofNOX4ROSlevelControlNaOHDMSOHypericinGlucosePMAROSlevelControlGlucoseDPIApocininSchematicillustrationofROS-medi