Post on 23-Aug-2020
VASCULAR DYSFUNCTION IN METABOLIC SYNDROME: THE ROLE OF OXIDANT STRESS
Upa Kukongviriyapan, Ph.D.Department of Physiology, Faculty of Medicine
Cardiovascular Research GroupKhon Kaen University
Academic Meeting 2007
• Free radicals and their essential roles• Oxidative stress and antioxidant defense system• Metabolic syndrome and its relation to endothelial/
vascular dysfunction• Evaluation of vascular dysfunction• Summary
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Overview of Presentation
What are fWhat are freeree rradicaladicals?s?• Any species that possess one or more unpaired electrons & capable of independent existence. • O2 possesses 2 unpaired electron while N2 has no unpairedHydrogen peroxide and singlet O2 (low spin) are not radicals.
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ROSROS//RNSRNS inin BiologicalBiological SystemsSystems
LO2.= RO2.
LO2H = RO2H
Oxidant production and antioxidant defenses
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Cellular signalingHost defencesIntracellular mediators
Major Signalling Pathwaysin Regulating Cellular Responses.
• Heat-shock transcription factor 1 (HSF1)• Nuclear factor (NF)- B• Phosphoinositide 3-kinase (PI(3)K)/
Akt pathway• Extracellular signal-regulated kinase (ERK)• c-Jun amino-terminal kinase (JNK)• p38 mitogen-activated protein kinase
(MAPK) signalling cascades
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Oxidative Stress
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• An imbalance between anti-oxidant systems and pro-oxidant molecules (ROS/RNS)
PRO-OXIDANTSsuperoxide anionperoxynitriteoxidized glutathione hydrogen peroxidehydroxyl radicallipid peroxidesetc
ANTI-OXIDANTSSuperoxide dismutaseglutathione peroxidasecatalasevitamins E, C, Aetc
A failure to repair causes oxidative damage which has been implicated in “disease states”.
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DiabetesDyslipidemiaObesityHypertensionAtherosclerosisCAD/ MIHeart failure
Excessive or uncontrollable production of reactive species ensuesbiomolecular damages, cellular injury, cell dysfunction/death & organ dysfunction
ROS/RNS
BrainTrauma, strokeParkinsonDementia
JointRheumatoid arthritis
Skin
Gastrointestinal tractPancreatitisEndotoxin liver injuryIschemic bowel
EyeCataractogenesisretinopathy of prematurityDegenerative retinal damageCVS/Endocrine
LungAsthmaARDS
Kidneys
MultiorganInflammatory-immune injuryIschaemia-reflow statesIron overloadAlcohol toxicityNutritional deficienciesRadiationAgingTumor promotion/ CancerAmyloid diseases
BurnsSolar radiationPsoriasisDermatitis
TransplantationGlomerulonephritis
ErythrocytesThalassemiaFanconi anemiaMalaria
Metabolic Syndrome
• Clustering of Components:– Obesity (central)– Hypertriglyceridemia– Low HDL-cholesterol– Impaired Glucose Handling– Hypertension– Microalbuninuria (WHO)
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Metabolic Syndrome
Country Prevalence (%)
Chinese 11-27%India 29Iran 30.1Korea 11 Maxico 26.6 Omen 21Ireland 20.7Australia 18.3USA (White) 23.8USA (African America) 21.6USA (Maxico America) 31.9
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Worldwide prevalence of the metabolic syndrome
Cheung BMY and Thomas GN. Cardiovas & Hematol Disorder Drug Targets. 2007; 7: 79-85.
Thailand ~ 15%(Ponchaiyakul C, et al., 2007)
• World Health Organization• International Diabetes Federation (IDF) -
European Association for the Study of Diabetes (EASD)
• National Cholesterol Education Project, Adult Treatment Panel (NCEP-ATP III)
• Others
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Criteria for diagnosis
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Ritchie SA and Connell JMC. Nutrition, Metabolism & Cardiovascular Diseases 2007; 17:319-326.
Definitions of Metabolic Syndrome
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Metabolic syndrome diagnosis: ATP III emphasizes clinical practice
Risk factor Defining level
Abdominal obesity Waist (in/cm) Men >35 (90)Women >32 (80)
Triglycerides (mg/dL) ≥150
HDL-C (mg/dL)Men <40Women <50
BP (mm Hg) ≥130/ ≥85
Fasting glucose (mg/dL) ≥100
• Any three of the followings:
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Other markers of insulin resistance
• Family history of type 2 diabetes or CAD• Adiponectin• Overactive sympathetic nervous system• ↑apoB, apoC-III, Uric acid & PAI-1• ↑ pro-inflammatory cytokines• Endothelial dysfunction
Cohn GS et al. Am J Hypertens. 2005;18:1099-103.
Moens, et al., Chest 2005; 127: 2254-2263.
Insulin signalling via the PI3K-dependent pathwayin adipocytes and skeletal muscle.
Eriksson JW. FEBS Letters 2007; 581: 3734–3742. Academic Meeting 2007
Moens, et al., Chest 2005; 127: 2254-2263.
Novel biological effects of insulin
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Dandona P et al. Circulation 2005; 111: 1448-54.
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ROS accumulation as a unifying pathwayleading to insulin resistance.
Eriksson JW. FEBS Letters 2007; 581: 3734–3742.
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Development of insulin resistance and type 2 diabetes
Eriksson JW. FEBS Letters 2007; 581: 3734–3742.
Academic Meeting 2007Dandona P et al. Circulation 2005; 111: 1448-54.
Extension of metabolic syndrome on the basisof resistance to the novel actions of insulin
VasodilationGrowth inhibitionAnti-thrombosisAnti-inflammationAntioxidantImmunity
VasoconstrictionGrowth promotionPro-thrombosisPro-inflammationPro-oxidantImmune defect
The Vascular Endothelium
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pathological conditions
altered anticoagulant & anti-inflammatory properties
impaired modulation of vascular growth & dysregulation of vascular remodeling
“ An impairment of endothelium-dependent vasorelaxationcaused by a loss of NO bioactivity in the vessel wall.
Hypertension Obesity Dyslipidemia Diabetes Heart failureArtherosclerosis Vascular injury Thalassemia Cigarette smoking Aging
O2-
Oxidative stress
Endothelial dysfunction
Platelet aggregation Vascular lesion &remodeling
Loss of vasodilation
Inflammation Thrombosis
NO bioavailability
ROS
NOUncoulpled eNOSXanthine oxidaseNADP/NADPH oxidase
Cai & Harrison. CircRes 2000;87:840.Belhassen et al. Blood 2001;97:1584.Cheung et al. Ciculation2002;106:2561.
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(ONOO.-, LOO., LO., OH.)
BH4 oxidation
• Biomarkers of metabolic syndrome (DM, Dyslipidemia, HTN,Obsesity)• Biomarkers of antioxidant/oxidant stress
– Redox status: GSH/GSSG ratio– Antioxidant enzymes/non enzymes – Lipid peroxidation: MDA, F2 isoprostanes– Protein peroxidation: Carbonylated proteins – DNA damage: 8-OH-dG– 3-niro-tyrosine
• Biomarkers of endothelial/vascular dysfunction– Shear stress post-ischemic dilation
• Arterial diameter: Flow-mediated dilatation• Arterial flow: Forearm blood flow
– Arterial stiffness• Arterial compliance and waveform morphology
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Biomarkers of MS, Oxidant stress & Vasc dysfunction
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Shear Stress-Induced Flow-Mediated Dilatation
Moens et al. Chest 2005; 127: 2254-2263
Technical aspect of Flow-Mediated Dilatation(Ultrasound technique)
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OBESITY RESEARCH 2003; 11: 1278-89.
Endothelial Dysfunction in Obesity and InsulinResistance: A Road to Diabetes and Heart Disease.By: A. Enrique Caballero
(n=30)(n=39) (n=32)
(n=42)
Impaired endothelium-dependent vasodilation in people at risk fortype 2 diabetes.
(n=30)
(n=39)(n=32)
(n=42)
• The technique evaluates the percentage change of flow from baseline to the maximum flow during “reactive hyperaemia” following a 4-5 minutes ischaemiaof the forearm.
• The initial rate of swelling represents the arterial inflow.
Technical aspect of Forearm blood flow(Strain-gauge plethysmographic technique)
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Vascular Stiffness: Arterial Pulse Waves(Ultrasound/ plethysmographic technique)
Greenwald SE. J Pathol 2007; 211: 157-172.
PWV (m/s)Aix = (a/a+b)x100 (%)
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PWV (mean and SD) in men and women with or withoutmetabolic syndrome, according to the NCEP.
N=96/sex/group
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Baselines Adjusted Values and Change (Δ) in PWV Accordingto the Number of Anomalies (0, 1, 2, 3 . . . ) of CV risk factors.
The CV risk factors: hypertension, BMI, dyslipedemia, hypertriglyceridemia , hyperglycemia.
Safar ME., et al., J Am Coll Cardiol 2006; 47: 72-5.
•• Treat the targets of diseases (DM, Hypertension, Obesity & dyslipidemia)
• Reduce oxidative stress by keeping healthy diet and lifestye modifications.
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Summary
Thank you!Thank you!
Schematic diagram of the effect of the endogenous AOX status on the response to injury
Origin of the most common nutritional AOX in food
The general role of antioxidants, lycopene, PJ, wine, andomega 3-PUFAs in the disruption of oxidation-sensitive events
Table 2 (continued)
Healthy dietary patterns contribute to a lower generation of aproinflammatory milieu, which in turn may decrease the incidence ofmetabolic syndrome, type 2 diabetes, and coronary heart disease (CHD).
Different effects of physical exercise on redox status of the cell.
Timetable of FMD(Ultrasound technique)
Timetable of FBF(Strain-gauge plethysmography)
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Insulin resistance increases risk of target organ damage in hypertension
Patients(%)
Leoncini G et al. J Intern Med. 2005;257:454-60.
10
40
19
59
0
15
30
45
60
Microalbuminuria* LV hypertrophy
With insulin resistance syndrome*Without insulin resistance syndrome*
P = 0.04
P = 0.003N = 354 with untreated hypertension
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IDF ethnic- and gender-specific criteria for central obesity
European ≥ 37 (94) ≥ 32 (80)Sub-Saharan AfricanMiddle Eastern
South Asian ≥ 35 (90) ≥ 32 (80)South/Central American
Chinese ≥ 35 (90) ≥ 32 (80)
Japanese ≥ 34 (85) ≥ 35 (90)
Waist circumference (inches & cm)Men Women
Alberti KG et al. Lancet 2005; 366: 1059-62.
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Type 2 diabetes and glycemic disorders
Dyslipidemia– Low HDL– Small, dense LDL– Hypertriglyceridemia
Hypertension
Endothelial dysfunction/inflammation (hsCRP)
Impaired thrombolysis↑ PAI-1
VisceralObesity
Insulinresistance
Glucotoxicity
Lipotoxicity
↓ Adiponectin
Atherosclerosis
Clinical manifestations of insulin resistance
By: Selwyn AP, Weissman PN.
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VisceralObesity
↑ Caloricintake
Sedentarylifestyle
Geneticfactors
↑ Freefatty acids
↑ Glucose
↑ Lipids
Oxidativestress
Inflammation
Insulinresistance
Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.
Role of obesity in insulin resistance
Different effects of physical exercise on redox status of the cell.
http:/www.tmd.ac.jp/mri/prm/englishi1-10/slide2.jpg
Cell injury
Oxidative damage- lipid- protein- DNA
OH•
H2O + O2Catalase
GPx/GSHH2O2
MPO
NO
O2 e-
• NDAPH oxidation• Oxidation of xanthine/hypoxantine• Oxidation of reducing equivalents• Autoxidation of monamines,flavins,Hb• Cytochrome P450
O2•-
ONOO-
PeroxynitriteHOONO
Peroxynitrous acid
O2•-
NO2•
nitrogen dioxide radical
+
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Oxidative stress/Oxidative stress/AntioxidantAntioxidant defensedefense
High use of O2 and glucoseActivation: iNOS, XO, NAD(P)H oxidase,High Fe/ascorbateHigh peroxidizable fatty acidsRedox cycling chemicals
Antioxidant agents:Remove free radicals and other reactive species
enzymatic method: SOD, CAT, GPx, etcradical scavenger: Vit. E, C, beta-carotene, flavonoids
Minimize the availability of pro-oxidants: metal chelators; transferrin, ferritin, ceruloplasmin
Protect biomolecule against damage: chaperon protein: heat shock proteins
Enzyme antioxidants:SOD, CAT, Gpx, GR, TrxR, PrxNon-enzyme antioxidants:GSH, ascorbate, vitamin Ebeta-carotene, urate, bilirubin, ferritin
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