5糖尿病血管疾病并发症课件.ppt

5糖尿病血管疾病并发症AGEs形成过程5糖尿病血管疾病并发症2.AGEs参与糖尿病血管损伤的证据2型糖尿病肾病肾动脉切片，免疫组化显示肾动脉壁中有AGEs沉积（棕色）5糖尿病血管疾病并发症EricJ.Topol,etal.ReceptorforAGE(RAGE)MediatesNeointimalFormationinResponsetoArterialInjury.Circulation.2003;107(17):2238-2243A片正常鼠颈动脉切片；内膜及中层无明显AGEs沉积（免疫组化）B片为糖尿病鼠颈动脉切片；内膜及中层有明显AGEs沉积（褐色）AB5糖尿病血管疾病并发症胰岛素抵抗患者，糖化血红蛋白与左室重量、主动脉硬化相关。DimitriosAStakos,DaraPSchuster1,ElizabethASparks2,etal.Associationbetweenglycosylatedhemoglobin,leftventricularmassandaorticfunctioninnondiabeticindividualswithinsulinresistanceEuropeanJournalofEndocrinology,2007,Vol157,Issue1,63-685糖尿病血管疾病并发症A片:非糖尿病肾切片；肾小球血管中无AGEs沉积（免疫组化）B片:糖尿病患者肾切片；肾小球血管中有明显AGEs沉积（棕色）AB5糖尿病血管疾病并发症糖尿病肾组织切片,肾小球血管及肾小球内新月体有明显AGEs沉积（免疫组化，深棕色为阳性信号）5糖尿病血管疾病并发症3.AGEs致大血管损伤的基本机制1)大分子交联物AGEs在动脉壁内的沉积,降低脉管的弹性2)AGEs灭活内皮源性NO血管扩张缺陷BucalaR,TraceyKJ,CeramiA.Advancedglycosylationproductsquenchnitricoxideandmediatedefectiveendothelium-dependentvasodilatationinexperimentaldiabetes.JClinInvest1991;87:432-8.5糖尿病血管疾病并发症3)AGEs修饰LDLLDL清除正常ApoB、E可与LDL受体和LDL受体相关蛋白结合，糖化ApoB、E不能结合LDL受体BucalaR,MitchellR,ArnoldK,etal.IdentificationofthemajorsiteofapolipoproteinBmodificationbyadvancedglycosylationendproductsblockinguptakebythelowdensitylipoproteinreceptor.JBiolChem1995;270:10828-32.5糖尿病血管疾病并发症4)AGEs作用于RAGENF-kB激活表达ICAM-1MCP-1PAI-1组织因子VEGFVCAM-1Jean-LucWautier,AnnMarieSchmidt.ProteinGlycationAFirmLinktoEndothelialCellDysfunction.CirculationResearch.2004;95（3）:233VlassaraH,FuhH,DonnellyT,etal.Advancedglycationendproductspromoteadhesionmolecule(VCAM-1,ICAM-1)expressionand