These ppt explain about the disease of vessels

1. Atherosclerosis
Jana Novotná

2. Atherosclerosis
 Disease of cardiovascular system affecting
vessel wall.
 It leads to the narrowing of arteries or
complete blockage.
 Its main components are endothelial
disfunction, lipid deposition, inflammatory
reaction in the vascular wall.
 Remodeling of vessel wall.

3. Atherosclerosis
 Intense cross-talk between EC, VSMC,
plasma-derived inflammatory cells,
lymphocytes (involves array of chemokines,
cytokines, growth factors).
 Attraction of cells to the sites of
atherosclerotic lesion.
 Migration, proliferation, apoptosis, excess
production of extracellular matrix.

4. Arterial wall
 Normally arterial endothelium repels
cells and inhibits blood clotting.
 The lumen of healthy arterial wall is
lined by confluent layer of endothelial
cells.

5. Arterial wall
 Three layers:
1. Intima (subendothelial layer)
2. Media (middle layer) with smooth
muscle cells (VSMC)
3. Adventitia (outer layer) with
connective tissue and nerves

6. Arterial wall
 Endothelium controls important
function:
1. the ability of blood vessels to dilatate
(vasodilatation)
2. the ability of blood vessels to
constrict (vasoconstriction)
 Endothelium regulates tissue and organ
blood flow.

7. Arterial wall
 Endothelium releases variety substances to control vasomotor
tone:
 prostacyclines
 hyperpolarizing factor
 endothelin
 NO
 Exercise is an important mechanical stimulus mediated by shear
stress to increased blood flow.
 Shear stress –represents the frictional force that the flow of
blood exerts at the endothelial surface of the vessel wall. The
flow-dependent dilatation of pre-capillary resistance as well as
conductance allows blood flow to increase according metabolic
demands.

8. Arterial wall
 In the case of intact endothelium, the stimulus for
vasodilatation:
 mechanical stimulation by  blood flow
 catecholamines, bradykinin, platelets-released serotonin
stimulate specific receptors
 In the case of endothelium disfunction:
 direct vasoconstrictor action of the stimuli on the VSMC
outweighs the endothelium-dependent vasodilatator effect
 this action leads to paradoxial vasoconstriction
(Hypercholesterolemia and other cardiovascular risk factors are
associated with endothelial disfunction).

9.  Factor which controls vasodilatation: endothelium-
derived relaxing factor (EDRF)
 The activity of eNOS is controlled by intracellular Ca2+.
 eNOS – endothelial constitutive enzyme (continually
expressed) and iNOS inducible, from VSMC.
 NO cause vasodilatation via stimulation guanylate
cyclase and cGMP production.
Nitric oxide (NO)
Arginine NO + citrulline
O2 + NADPH NADP+

10. The development of
atherosclerosis
 The key event – damage to the endothelium caused
by excess of lipoproteins, hypertension, diabetes,
components of cigarette smoke.
 Endothelium becomes more permeable to
lipoproteins.
 Lipoproteins move below the endothelial layer (to
intima).
 Endothelium loses its cell-repelent quality.
 Inflammatory cells move itno the vascular wall.

11. The scheme of LDL a HDL

12. Triggers for inflammation in
atherosclerosis
 LDL retained in the intima (in part by binding
to proteoglycan) undergoes oxidative
modification.
 Lipid hydroperoxides, lysophospholipides,
carbonyl compounds localize in the lipid
fraction.
 Oxygen free-radicals inactivate NO rapidly.
 NO + superoxide (O2
.-)  peroxynitrite
(ONOO-).
 NO has no longer vasoprotective function.

13. The development of
atherosclerosis
 Disfunctional endothelium express adhesion molecules –
selectins, mediated the „rolling“ interaction of cells.
 The key molecule - vascular cell addhesion molecule-1
(VCAM-1) promotes monocytes adhesion (precursors of
macrophages).
 Addhering cells are stimulated by monocyte
chemoattractant protein-1 (MCP-1).
 Monocytes cross the endothelium, settle down in the intima.

14. NO inactivation due to
oxidative stress
Schächinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055
• Xanthin oxidase and
NADH/NADPH oxidase produces
of O2
.- in macrophages after
stimulation with angiotensin II
(a key mediator of oxidative
stress in vascular wall).
• In the early stage of process,
ROS are released from
endothelium.
• In the later atherogenetic
process, ROS are produced by
macrophages in thickening
vessel wall.

15. Triggers for inflammation in
atherosclerosis
 Reduced NO bioactivity, increased oxidative stress
leads to tyrosine nitration of protein in vessel wall.
 Nitrotyrosine and oxidized LDL activate transkriptional
factor NF-kB (nuclear factor kappa-light-chain-enhancer of
activated B cells).
 NF-kB increases proliferation of VSMC
 Reduced NO bioactivity and enhanced oxidative
stress stimulate cytokine production (interleukins,
TNFa, MCP-1, interferons) and monocytes attraction.

16. Inflammation in atherosclerosis
(mononuclear cells)
Fom the review article: Libby P.: Inflammation in atherosclerosis. Nature 420, 2002: 868-874
Endothelial cells undergo inflammatory activation, produce different leukocyte adhesion
molecules (VCAM-1). Monocytes penetrate into tunica intima. Their receptor CCR2 interact
with MCP-1
• Resident monocytes
acquire characteristics of
tissue macrophages.
• Macrophages express
scavenger receptors for
oxidized LDL,
internalized lipoprotein
particles. Macrophages
change to foam cells
(lipid droplets are
accumulated within the
cytoplasm).
• Foam cells secrete pro-
inflammatory cytokines.
• This process amplify
local inflammation and
ROS.

17. Inflammation in
atherosclerosis (T-lymhocytes)
Fom the review article: Libby P.: Inflammation in atherosclerosis. Nature 420, 2002: 868-874
T-lymphocytes enter the intima facilitated by VCAM-1 and trio chemokines- IP-10 (inducible
protein-1), Mig (monokine induced by interferon-g) and I-TAC (interferon-inducible T-cells a-
chemoattractant). Trio chemokines bind to CXCR3 chemokine receptor expressed by T-cells in
the atherogenic lesion.
T-cells are activated by
antigens (Ox-LDL, heat-
shock proteins),
produce cytokines.
Cytokines influence
behaviour of other cells
present in the
atheroma.
CD154 (protein
expressed on activated
T-cells) binding to CD40
ligand expressed on
macrophages induces
the epression of other
cytokines, MMPs, tissue
factor.

18. Inflammation in
atherosclerosis (mast cells)
Fom the review article: Libby P.: Inflammation in atherosclerosis. Nature 420, 2002: 868-874
Mast cells infiltrate to the intima. Chemoattractant eotaxin mediate migration of
mast cells and interacts with the chemokine receptor CCR3. Resident mast cells in
the intima degranulate, release TNF-a, heparin, and enzymes activating
proMMPs.

19. The process of atherogenesis – an overview

20. The process of atherogenesis
 Lipid entry into the arterial wall is a key process in
atherogenesis.
 Hypercholesterolemia – factor for VCAM-1 and MCP-1
induction.
 LDL and VLDL are most atherogenic, enter vascular
wall more easily.
 LDL – in plasma are protected against oxidation by
vit. E, ubiquinon, plasma antioxidants (b-carotene,
vit. C).
 Out of plasma, LDL phospholipides and fatty acids
oxidize.

21. The process of atherogenesis
 Activated macrophages produce enzymes –
lipoxygenases, myeloperoxidase, NADPH oxidase 
ROS
 Oxidized LDL are cytotoxic to endothelial cells,
mitogenic for macrophages.
 Oxidized LDL apolipoprotein apoB100 bind to the
scavenger receptor.
 Scavenger receptors are not subjected to regulation
by intracellular cholesterol level.
 Macrophages take up oxidized LDL, overload with
lipids.

22. The process of atherogenesis
 Foam cells ruptured (apoptosis).
 Lipid release to intima and their acumulation
becomes centre of atherosclerotic plaques.
• The lipid center and fibrous
cap are the main parts of a
mature atherosclerotic plaque.
• Plaque emerges from the
structurally changed vascular
wall.
• So-called vulnerable plaque
ruptures easily.
•The thrombus formed at the
rupture site.

23. The process of atherogenesis
 Plaque growth – periodically accelerated by a
cycle of plaque rupture and thrombosis.
 This happens:
 Active macrophages and T lymphocytes
preferentially reside at the edge of the plaque.
 Macrophages secrete enzymes degrade
extracellular matrix of the cap (MMP –
collagenases, gelatinases, and stromelysin)
 T-cells activated by macrophages secrete IFN-g
and pro-inflammatory cytokines IL-1, IL-2, and
TNF-a.

24. The process of atherogenesis

25. The process of atherogenesis
 IFN-g induces macrophage MMP expression.
 IFN-g inhibits VSMC proliferation and collagen synthesis which
further weakening the cap.
 VSMC undergo apoptosis.
 After plaque rupture the area is exposed its interior to the
blood.
 The interior of the plaque is highly thrombogenic – the small-
molecular-weight glycoprotein (tissue factor) initiates the
extrinsic clotting cascade.
 Tissue factor complexes with factor VII/VIIa, factor IX and X are
activated.
 Platelets are activated and thrombus forms quickly on the
surface of a ruptured plaque.
 Thrombus completely occludes the arterial lumen. It cause
tissue necrosis (myocardial infarction or brain stroke).

26. Cardiovascular risk and its
assesment
 Plasma concentration of lipoproteins
(LDL-cholesterol, HDL-cholesterol, and
triacylglycerols) –  5.2 mmol/L (200
mg/dL) increases the risk.
 Optimal level of LDL-cholesterol - 2.6
mmol/L (100 mg/dL)

27. Cardiovascular risk and its
assesment
The risk of atherosclerotic event can be decreased by:
 Cholesterol low diet
 Exercise
 Smoking cessation
 Control of high pressure
 Drugs statins, fibrates (fibric acid), ezetimibe, antioxidants
Statins – inhibit intracellular cholesterol synthase (HMG-CoA
reductase).
Fibrates - lower plasma cholesterol by stimulating LPL, decreasing
TAG concentration, and increasing HDL.
Ezetimibe – inhibitor of intestinal cholesterol transporter.
b-carotene, a-tocoferol, vitamin C (such as these contained in fruits
or their combinations) have preventive benefit, protect LDL against
oxidation.

28. Schächinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055