VASCULAR DYSFUNCTION IN METABOLIC SYNDROME: THE …2017/Yupa_Oxidative_M… · • Metabolic syndrome and its relation to endothelial/ vascular dysfunction • Evaluation of vascular

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


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.



ROSROS//RNSRNS inin BiologicalBiological SystemsSystems

LO2.= RO2.

LO2H = RO2H

Oxidant production and antioxidant defenses


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


Oxidative Stress


• 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”.


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)


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


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


Criteria for diagnosis


Ritchie SA and Connell JMC. Nutrition, Metabolism & Cardiovascular Diseases 2007; 17:319-326.

Definitions of Metabolic Syndrome


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:


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


Dandona P et al. Circulation 2005; 111: 1448-54.


ROS accumulation as a unifying pathwayleading to insulin resistance.

Eriksson JW. FEBS Letters 2007; 581: 3734–3742.


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


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.


(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


Biomarkers of MS, Oxidant stress & Vasc dysfunction


Shear Stress-Induced Flow-Mediated Dilatation

Moens et al. Chest 2005; 127: 2254-2263

Technical aspect of Flow-Mediated Dilatation(Ultrasound technique)



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)




Vascular Stiffness: Arterial Pulse Waves(Ultrasound/ plethysmographic technique)

Greenwald SE. J Pathol 2007; 211: 157-172.

PWV (m/s)Aix = (a/a+b)x100 (%)


PWV (mean and SD) in men and women with or withoutmetabolic syndrome, according to the NCEP.

N=96/sex/group


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.


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)



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


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.


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.


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

+


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


Documents

VASCULAR DYSFUNCTION IN METABOLIC SYNDROME: THE …2017/Yupa_Oxidative_M… · • Metabolic syndrome and its relation to endothelial/ vascular dysfunction • Evaluation of vascular