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 glucose  12-LO & 12-HETE  Lipoxigenase(LO) 15-LO 12-LO VSMC migration LO 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 itself  free 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 HG  adhesion&transmigration of monocytes HG  superoxide   endothelial disfunction HG  endothelial cell growth  glutathione, SOD, catalase

Association of free radicals and advanced glycosylation end products glucose+protein  glycosylation products (Schiff bases&Amadori products) H 2 O 2 sources of superoxide radical Amadori product  carboxymethyl-lysine  free radical reaction  AGEs  OS   NF-kB   endothelin-1&tissue factor  endothelial disfunction V-E completely SOD partially  LPO  -catalyzed by glycated polylysine catalase----no

HG  AGE  13.8fold in endothelial cell HG or AGE  apoptosis  -----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 DM  thiobarbituric 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 AGEs  NO 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  (hyperglycemia  DM 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 Q 10  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

HG  inflammation, OS  monocyte 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 proteins  C reactive protein(CRP) Inflammatory stimuli endothelial cell monocyte interaction AP-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