Chp101Oxidative 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

• glucose 12-LO & 12-HETE

Lipoxigenase(LO)•15-LO•12-LO • VSMC migrationLO product--- HPETEs PKC, oncogene activation• HTETs 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

NOS---

NO synthases (NOS)

Endothelium & other

• inducible NOS(iNOS or typeII)• neuronal NOS(ncNOS or typeI)• endothelial NOS(eNOS or typeIII)

low-oxidized LDL phy-insulin eNOS sex hormones proinflammatory cytokines eNOS (TNF-a)

그림 101.2

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 free radical NADPH/NAD+

※ NADPH/NAD+ change in vascular permeability&flow • high glucose(HG) LO(expression&activity) endothelial cell 15-HETE HG VSMC growth HG 12-LO • signal transduction HG PKC • • MAPK, ERK1/2, C-jun amino-terminal kinase, p38 MAPK, AP-1, NF-kB

Sorbitol pathway

LO inhibitor

• 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-lysine• free radical reaction • AGEsOSNF-kBendothelin-1&tissue factor endothelial disfunction V-E-------completely SOD-------partially LPO-catalyzed by glycated polylysine catalase----no

• HGAGE13.8fold ----- in endothelial cell

• HG or AGEapoptosis -----in HUVAC cell inhibited by a-LA

• AGE inhibitor---diabetic complications

Evidence for an enhanced oxidative stateIn diabetes mellitus

DM-OS •uncontrolled DM--SOD

•type1DM--------superoxide anion production -LDL oxidation antioxidant defence

• poorly controlled type2 DMthiobarbituric acid

• 적혈구 막 T1DM----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 NO production NOS (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 adhesionAtherosclerotic plaque rupture

• HGinflammation, OSmonocyte adhesion

• endothelial cell IL-8

• 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)

Inflammatory stimuli

endothelial cell monocyte intera

ctionAP-1,CHO-RE Oxidized LDL, TNF-a

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