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1、Increased activity and expression of NADPH oxidase 4 stimulated by glucose induces oxidative stress in vascular endothelial cellsJian LIJian LIKey Laboratory of Geriatrics, Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Ministry of Health, Beijing Institute of Geriatrics, Ministry of
2、 Health, Beijing 100730, ChinaBeijing 100730, China-cellliverobesity-Cell DysfunctionInsulin ResistanceFFA VLDLFFA VLDL GlucoseOxidative stressHypothesisHypothesis Redox rheostat“ in cells Where are reactive oxygen species generated?Where are reactive oxygen species generated?Mitochondrial respirtio
3、n-chain enzyme complexxanthine oxidase, NOS, lipoxygenasePhagocyte NADPH oxidase NADPH oxidase of non-phagocytic cellsNADPH oxidase is a major source of vascular ROS production.NOX-type NADPH oxidasesas superoxide-producing enzymes FeFeoutsideinsideIVIIVIIIIIVNH2HHHHHHNADPHFADCOOHH115O2O2-e-Structur
4、e of the NADPH oxidaseThe NOX family of NADPH oxidasesgp91phox homologyEF-handsNox1 colonNox2 phagocytesNox3 inner earNox4 kidney and vascular cellsNox5 testis and lymphoid tissuesO2O2-NADPHe-A AB BC CD DDPI:NOXDPI:NOX inhibitor; Rotenone: inhibitor; Rotenone: inhibitor of mitochondrial respirtion-c
5、hain enzyme complex; L-NAME:NOS inhibitor; L-NAME:NOS inhibitor; Oxypurinol:Oxypurinol: xanthine oxidase inhibitor NADPH oxidase is a major source of vascular ROS production induced by glucoseA: negative control; A: negative control; B: HUVEC;B: HUVEC;C: 20mM glucose treated HUVEC;C: 20mM glucose tr
6、eated HUVEC;D: positive controlD: positive control Glucose induces apoptosis of HUVECA AG GC CC CG GC CG GC:HUVEC; G:20mM glucose-treated HUVECWestern blotGlucose up-regulates the expression of NOX4-actinNOX4 NOX2 p22phox p47phox p67phox Rac 1 M A N1 N2 N3 N4 p22 p47 p67 Rac1RT-PCR 0 10 20 30 glucos
7、e(mM) A: negative control; B: transfected with GFP-pcDNA3.1; C: transfected with NOX4-pcDNA3.1 Over-expression of NOX4 increases Over-expression of NOX4 increases the level of ROSthe level of ROS and results in apoptosisand results in apoptosisA AB BC CA AB BC CA AB BC CA AB BC CNOX4-siRNA decreases
8、 the expression of NOX4-siRNA decreases the expression of NOX4 and the level ROS in HUVECNOX4 and the level ROS in HUVECC C+G S-FAM S-FAM+G S-NOX4 S-NOX4+G C S-FAM S-NOX4*Mechanism for increased ROS production Mechanism for increased ROS production induced by diabetes and insulin-resistant stateindu
9、ced by diabetes and insulin-resistant stateDiabetesHigh glucose levelInsulin resistanceObesityElevated NEFA levelDe novo DAG synthesisVascular cellsPKC activationNADPH oxidase activationSuperoxideROSActivation of NADPH oxidase Immunoflurescence staining of p47phoxPKC/p47phox regulates the activation
10、 of NOX4PKC/p47phox regulates the activation of NOX4ROS levelROS levelControlNaOHDMSOHypericinGlucosePMAROS levelROS levelControlGlucoseDPIApocininSchematic illustration of ROS-mediated NFB activationSchematic illustration of ROS-mediated NFB activationGlucose activates NFB pathway C GC G -actin p-N
11、F BNF BI B p-I BVCAM-1 ICAM-1 C G G+DPINF BDAPIMerge C G G+SBC G G+SB Glucose activates p38MAPK pathwayP-p38MAPKp38 MAPK-actin C G G+SB203580 C G G+SB203580 Western blot Hochest/PI staining Hochest/PI staining Immunofluorescence C G G+SB203580 C G G+SB203580 Anti-oxidation agents for the oxidative d
12、amage of vascular endothelial cells high glucose levelPKC activationPKC inhibitorAngiotensin IINAD(P)H oxidaseactivationStatinsARBACEIHDLProbucolSimvastatin Simvastatin decreases the level of MDAdecreases the level of MDA and TGand TG in the atherosclerosis model of apo E-/- micein the atheroscleros
13、is model of apo E-/- mice*MDATCTGSOD*Simvastatin Simvastatin suppresses the generation of ROS suppresses the generation of ROS and expression of NOX in and expression of NOX in atherosclerotic atherosclerotic plaqueplaquecontrolcontrolSimvastatin treatmentSimvastatin treatmentROSROSNOX2NOX2p47PHOXp4
14、7PHOXNOX4NOX4Simvastatin Simvastatin has the ability to has the ability to stabilize the vulnerable atherosclerotic plaquestabilize the vulnerable atherosclerotic plaquecontrolcontrolSimvastatin treatmentSimvastatin treatmentThe area of AS lesionThe area of AS lesionThe thickness of fibrous cap The thickness of fibrous cap The content of collagenThe content of collagenThank you!
