Oxidative Stress and Atherosclerosis
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Oxidative Stress and Atherosclerosis. Objectives:. What is „free radical“? Reactive oxygen and nitrogen species (RONS) Are the RONS always dangerous? Well known term „oxidative stress“ - what is it? Antioxidants - types Disorders Associated with Oxidative stres s

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Objectives
Objectives:

What is „free radical“?

Reactive oxygen and nitrogen species (RONS)

Are the RONS always dangerous?

Well known term „oxidative stress“ - what is it?

Antioxidants - types

Disorders Associated with Oxidative stress

Oxidative stress and atherosclerosis


Basics of Redox Chemistry

Term Definition

Oxidation Gain in oxygen

Loss of hydrogen

Loss of electrons

Reduction Loss of oxygen

Gain of hydrogen

Gain of electrons

Oxidant Oxidizes another chemical by taking

electrons, hydrogen, or by adding oxygen

Reductant Reduces another chemical by supplying

electrons, hydrogen, or by removing oxygen


Reactive Species

R3C.Carbon-centered

R3N.Nitrogen-centered

R-O.Oxygen-centered

R-S.Sulfur-centered

  • Free Radicals:

  • A molecule with an unpaired electron in an outer valence shell

  • tend to reach equilibrium, plucks an electron from the nearest intact molecule.

  • most of biomoleculsare not radicals

H2O2Hydrogen peroxide

HOCl- Hypochlorous acid

O3Ozone

1O2 Singlet oxygen

ONOO- Peroxynitrite

Men+ Transition metals

Radicals are highlyreactivespecies

  • Non-Radicals:

  • Species that have strong oxidizing potential

  • Species that favor the formation of strong oxidants (e.g., transition metals)


Reactive Oxygen Species (ROS)

Radicals:

O2.- Superoxide

.OH Hydroxyl

RO2. Peroxyl

RO. Alkoxyl

HO2.Hydroperoxyl

Non-Radicals:

H2O2Hydrogen peroxide

HOCl- Hypochlorous acid


Reactive Nitrogen Species (RNS)

Radicals as:

NO. Nitric Oxide

NO2.Nitrogen dioxide

Non-Radicals as:

Peroxynitrite


Oxidative Stress

Antioxidants

Oxidants

“An imbalance favoring (pro)oxidants and/or disfavoring antioxidants, potentially leading to damage” -H. Sies


Oxidative Stress

  • It is a state in the cells in which there is increased concentration of reactive species which is not counterbalanced by increased levels of antioxidants.

  • This imbalance was implicated in production of different diseases as atherosclerosis


Microsomal Oxidation,

Flavoproteins, CYP enzymes

Myeloperoxidase

(phagocytes)

Xanthine Oxidase,

NOS isoforms

Endoplasmic Reticulum

Transition metals

Lysosomes

Cytoplasm

Fe

Cu

Oxidases,

Flavoproteins

Peroxisomes

Mitochondria

Plasma Membrane

Electron transport

Lipoxygenases,

Prostaglandin synthase

NADPH oxidase

Endogenous sources of ROS and RNS


Reactive Oxygen Species (ROS)

  • O2. , H2O2 , OH. By partial reduction of molecular oxygen in electron transport chain in mitochondria

Oxygen-derived Free radicals: e.g., Superoxide and hydroxyl radicals

Non-free radical: Hydrogen peroxide


Antioxidants
Antioxidants

Enzymes:

Superoxide dismutase

Catalase

Glutathione system(glutathione, NADPH, reductase, peroxidase & selenium)

Vitamins:

Vitamin C (ascorbic acid)

Vitamin A and β-carotenes

Vitamin E

Trace elements:

Selenium





Nitric oxide no
Nitric Oxide (NO)

NO: Freeradicalgas Very short half-life (seconds) Metabolized into nitrates&nitrites and perooxynitrite

Synthesis: Enzyme: NO synthasePrecursor: L-Arginine

Effects:Relaxes vascular smooth muscle Prevents platelet aggregation Bactricidal & Tumoricidal effects Neurotransmitter in brain


Nos nitric oxide synthase
NOS ( nitric oxide synthase)

  • 2 constitiutive NOS:

  • are calcium-calmodulin dependent and

  • constantly produce low level of NO

  • ( primarly in endothelium=eNOS, neural=nNOS).

  • 1 inducible NOS :

  • calcium independent

  • can be expressed in many cells including hepatocytes, macrophages and neutrophils.

  • The inducers include bacterial toxins, tumor-necrosis factor and inflammatory cytokines

  • It can produce large amounts of NO over hours or even days


NO• signaling in physiology

Nitric Oxide Synthase

NO•

Binds to heme moiety of guanylate cyclase

Conformational change of the enzyme

Increased activity (production of cGMP)

Modulation of activity of other proteins (protein kinases, phospho-diesterases, ion channels)

Physiological response (relaxation of smooth muscles, inhibition of platelet aggregation, etc.)

O2-•

ONOO-


Oxidative stress role of nitric oxide no
Oxidative Stress: Role of Nitric Oxide (NO)

NO produced by endothelial NOS(eNOS) improving vascular dilation and perfusion (i.e., beneficial).

Vasodilators such as nitroglycerin is metabolized into NO and causes vasodilatation

Increased iNOS activity is generally associated with inflammatory processes


Oxidative Stress

Lipids Proteins DNA

Oxidation of

vitamin E

Thiol oxidation

Carbonyl formation

DNA damage

Altered gene

expression

Damage to Ca2+ and

other ion transport

systems

Lipid peroxidation

Membrane damage

Disruption of normal

ion gradients

Depletion of ATP

and NAD(P)H

Activation/deactivation

of various enzyme systems

Cell Injury

Adapted from: Kehrer JP, 1993


Consequences of lipid peroxidation

(polyunsaturated fatty acids)

  • Structural changes in membranes

    • alter fluidity and channels

    • alter membrane-bound signaling proteins

    • increases ion permeability

  • Lipid peroxidation products form adducts/crosslinks with non lipids

    • e.g., proteins and DNA

  • Cause direct toxicity of lipid peroxidation products

  • Disruptions in membrane-dependent signaling


Vascular effects of ros
Vascular effects of ROS:

  • Altered vascular tone

  • Increased endothelial cell permeability


Pathologicalconditions that involve

oxidative stress

  • Inflammation

  • Atherosclerosis

  • Ischemia/reperfusion injury

  • Cancer

  • Aging

  • Obesity


Pathogenesis of Atherosclerosis

  • Modified (oxidized) LDL … Oxidative stress (imbalance between oxidants and antioxidants)

  • Endothelial injury of arterial wall

  • Adherence of monocytes to endothelial cells and their movement into intima where it becomes macrophages

  • Uptake of oxLDL by macrophage scavenger receptor:Scavenger receptor class A (SR-A)

  • Low-affinity, non-specific receptor

  • Un-regulated receptor

  • Foam cell transformation: Accumulation of excess lipids inside the cells (unregulated receptor)

  • Atherosclerotic plaque formation


Athersclerotic Plaque Formation

Un-regulated LDL Uptake


Regulated LDL Uptake

high-affinity, specific & tightly regulated

LDL-Receptor



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