Chp101 Oxidative stress, inflammation, and diabetes complications Free radical • 유익성-microorganisms&cancer cell • 유해성-damage of cellular structures and enzymes lipid peroxidation • superoxide anion • hydrogen peroxide • hydroxyl radical vascular 에 대한 영향 •Endothelial cell – direct toxic effects • VSMC – proliferation • arachiodonic or linoleic acid metabolism free radical & lipid peroxide Lipoxigenase(LO) •15-LO •12-LO LO product--- HPETEs HTETs • glucose 12-LO & 12-HETE • VSMC migration • PKC, oncogene activation VSMC hypertrophy, matrix production MAPKs • antioxidant OS & freeradical V-E V-C Glutathione Cysteine Methionine Ubiquinone Urate Penicillamine V-A Nitric oxide(NO) L-arginine NO Endothelium & other NOS--- • inducible NOS(iNOS or typeII) • neuronal NOS(ncNOS or typeI) • endothelial NOS(eNOS or typeIII) low-oxidized LDL phy-insulin sex hormones proinflammatory cytokines (TNF-a) eNOS eNOS 그림101.2 Oxidative state affect NO function Superoxide anion + No peroxinitride • hydroxyl radical • lipoprotein oxidation • apoptosis Mechanisms by which elevated glucose could lead to increased And diabetic complications • glucose autoxidation itselffree radical &NADPH/NAD+ HG&TNF-a have aditive effect on superoxide prooduction • glucose Sorbitol pathway free radical NADPH/NAD+ ※ NADPH/NAD+ change in vascular permeability&flow • high glucose(HG) LO(expression&activity) endothelial cell 15-HETE HG VSMC growth LO inhibitor HG 12-LO • signal transduction HG • PKC • MAPK, ERK1/2, C-jun amino-terminal kinase, p38 MAPK, AP-1, NF-kB • NF-kB regulates transcrition • vascular endothelial growth factor(VEGF) • proinflammatory cytokines(TNF-a, IL-1) • vascular cell adhesion molecule-1(VCAM-1) • advanced glycosylation end product(AGE) ※ HG OS NF-kB regulate gene expression • HG & endothelial cell • HGadhesion&transmigration of monocytes • HGsuperoxide endothelial disfunction • HGendothelial cell growth glutathione, SOD, catalase Association of free radicals and advanced glycosylation end products • glucose+proteinglycosylation products(Schiff bases&Amadori products) H2O2 sources of superoxide radical Amadori product • carboxymethyl-lysinefree radical reaction • AGEsOSNF-kBendothelin-1&tissue factor endothelial disfunction V-E-------completely SOD-------partially catalase----no LPO-catalyzed by glycated polylysine • HGAGE13.8fold ----- in endothelial cell • HG or AGEapoptosis -----in HUVAC cell inhibited by a-LA • AGE inhibitor---diabetic complications Evidence for an enhanced oxidative state In diabetes mellitus DM-OS •uncontrolled DM--SOD •type1DM--------superoxide anion production -LDL oxidation antioxidant defence • poorly controlled type2 DMthiobarbituric acid • 적혈구 막T1DM----LPO T2DM----lipid MDA (8~10fold) • 초기 DM renal desease-urinary excretion of 12-HETE • DM atherosclerosis-OS & 12-LO expression • poorly controlled T1DM-NF-kB antioxidant--NF-kB albuminuria ---NF-kB binding activity • DM---antioxidant defenses T1DM---total antioxidant capacity T1,2DM- SOD (2fold) T2DM- -glutathione • enhanced OS is present in target organs during the development of DM complications DM nephropathy---OS---NF-kB Nitric oxide: effects of diabetes mellitus • rat&rabbit HG-aorta relaxation NO reverse blockade of PKC & SOD • HG--ATPase reverse HG effect is secondary to NO L-arginine or sodium nitroprusside • STZ- DM rat - OS was associated with eNOS&nNOS • in human T2DM-NO action (hyperlipidemia, insulin resistance, hypertension, altered ions(Ca, Mg), • DM influence NO action and metabolism • superoxide anione+NO=peroxinitrite membrane damage&LPO • AGEsNO action • aminoguanidine(inhibitor of NO) AGE NOS NO production (no action) Normalizes DM-induced vascular dysfunction Therapeutic implications of antioxidants for the prevention of diabetic complications • OS (hyperglycemiaDM complication) ※ V-E prevent vascular disease in nondiabetic subject V-E- DM? ※ LA-NF-kB (induced by TNF-a and AGE) LA-OS prevent DM nephropathy, neuropathy, retinopathy ※ coenzyme Q10 superoxide improve endothelial function • insulin and vascular complication low PI3K eNOS vasodilation high c-myc, MAPK, cell growth may have proatherogenic action • diet and vascular complication oxidized lipids in the diet magnesium deficiency Inflammation and macrovascular diabetic complication Oxidised LDL, AGE, chronic infection IL-1, IL-6, TNF-a Increased monocyte adhesion Atherosclerotic plaque rupture • HGinflammation, OSmonocyte adhesion Inflammatory stimuli endothelial cell • endothelial cell IL-8 monocyte interaction AP-1,CHO-RE Oxidized LDL, TNF-a • adhesion molecular ※ ICAM, VCAM, E-selection, P-selection ※ ligands—LFA-1, Mac-1, VLA-4, PSGL-1 ※ soluble cell adhesion molecules (sCAMs)—T2DM death risk • TNF-a, IL-6 acute-phase proteinsC reactive protein(CRP) Marker Myocardial infarction and stroke Role of PPARs • PPAR- and proinflammatory cytokine atherosclerosis • TNF-a, IL-1a and , IL-6 decrease PPAR- in adipocytes IL-4 induces PPAR- in monocytes 9-and 13-HODE increase PPAR- mRNA in macrophages • TZDs effect • • • • ROS PAI-1 CCR2 VSMC proliferation Role of the Renin-Angiotensin system • angiotensin II AP-1, STAT family, NF-kB •ACE-inhibitor VCAM-1 in T2DM •ACE inhibitor myocardial infarction, stroke, cardiac arrest, heart failure, and mortality conclusion OS and inflammation have an important role in the development of Diabetic microvascular and macrovascular complications