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“Atherosclerosis is imposible
without cholesterol”.
А.N.Аnichkov’s conception, which was proved in
1915
Atherosclerosis is the variable combination of changes in arteries intimae, which consists of focal accumulation of lipids, complicated carbohydrates, blood substances, fibrous tissue and calcium, and associated with changes in media.
(WHO definition)
First experimental model of atherosclerosis was created on rabbits. Every day within 3-4 months Annickov added 10 g of Cholesterol in rabbits ration.
General structure of lipoprotein.There is a lipid drop inside (nucleus), containing
threeglicerides (TG) and cholesterol aethers (ACh). Membrane covers the nucleus, it consists of protein
(apoprotein, or apo-), phospholipids (PhL) and non-aether cholesterol (NACh)
non-aethercholesterol phospholipids
Cholesterolaethers
threeglicerides
Apoprotein
Kinds of the lipoproteins
Indexes ChM VLDLP, pre--LP
LDLP -LP
HDLP -LP
Diameter, nm 100 25-75 19-24 6-12
Chemical structure (%):
Ch general 0,5- 3 15-17 35-48 20-37
% aeter Ch 46 57 66-70 78
PhL 3-9 13-20 11-30 24-40
TG 80-95 50-70 5-10 3-5
Protein 1-2 5-12 14-25 45-55
Apoproteins A, B, C, E B, C B, C, E A, C, D, E
Аpо-В-receptorАpо-Е-receptor
(receptor connects one apoprotein B or apoprotein E particle of LDLP, is depended to Ch needs of the cell)
Brown and Goldstein had got Nobel bonus
into 1985
Role of LP in Cholesterol transport inside the cell. That is due to receptor-mediated mechanism.
It was discovered by American scientists M.Brown and J.Goldstein in 1973-1975
Skin fibroblast
Smooth muscles cell
Lymphocyte
Macrophage
Peculiarities Are made- in blood- extracellular space- in arterial wall
Modified LDLP
Properties1. They do not interact with
аpоВ- and аpоЕ-receptors
2. They interact with “scavenger ” – receptors. Entrance of LDLP inside the cell results from concentration difference (uncontrolled еndocytosis)LDLP changed
by free radicals
LDLP+Glucose
LDLP+Ig
LDLP+glucoseaminoglycane
Stimulate of Ig synthesis and autoimmune damage of
arteries
Stimulate smooth muscle cells proliferation
Stimulate macrophage haemotaxis into arterial wall
Conduce blood cells adhesion on endothelyocytes
Increase endothelyocytes permeability
LDLP+Glucose are made in the blood of patients who suffer from diabetes mellitus
That explains why 80 % patients, which suffer
from diabetes mellitus, died in the result of
atherosclerosis complications
Ch metabolism violation1. Hypercholesterolemia
2. Dislipoproteinemia
а) LDLP concentration
b) Kch = LDLP+VLDLP
HDLP
(high coefficient correlates
to higher probability of
atherosclerosis)
Endothelium damage 1. Hemodynamic factors
а) Local pressure on endotheliocytes leads to their displacement and damage
b) Turbulent motion of the blood
(arch of aorta, embranchment of arteries)
2. Immune complexes
ЕТHIOLOGY
There are persons who have normal concentration of LDLP but suffer from atherosclerosis!
Reducing of HDLP concentration is important
Antiatherosclerosis role of HDLP
1. Very easy penetration in to the intimae (due to apоprotein-А) and take out cholesterol
2. Reduce coming up of LDLP inside endotheliocytes
3. Retention of LDLP damage by free radicals
4. Increase prostacycline synthesis and and as a result decrease thrombocytes aggregation
5. Decrease proliferation of the smooth muscle cells, which is induced by LDLP
6. Decrease synthesis of glucoseaminoglycane by smooth muscle cells
1. Male2. Оbesity3. Hypokinesia4. Hyperthreeglyceridemia5. Using much
carbohydrates6. Diabetes mellitus in adult7. Genetical defect of Apo-
А synthesis8. Smoking
1. Female2. Physical activity3. Low body weight
4. Moderate alcohol use
Low level HDLP High level HDLP
1 STAGE –
“FOAM CELLS” PATHOGENESIS
Macrophages play main role:
1. They have “scavenger”-
receptors so Cholesterol
comes in macrophage only
due to concentration
difference
2. They can accumulate a lot
of Ch inside (this process is
controlled by HDLP only)
3. Changed LDLP stimulate
macrophages activity
Migration of macrophage in intimae
Scavenger
receptor
Decrease LDLP
concentration in intimae
Many macrophages change into “foam cells”
1 STAGE –
“FOAM CELLS”
Migration of macrophage in intimae
macrophage
foam cell
Figure. “FOAM CELL” macrophage origin, which was getting from aorta intimae of a human. Electron microscopy. Magnify 7000
1 STAGE –
“FOAM CELLS”
Role of endotheliocytesThere is no deposit of LDLP inside the endotheliocytes!!!!!!!!!а) Due to Аpо-В,Е-receptors entrants of LDLP is controlledб) Using of scavenger receptors stimulates retroendocytosis
But!!!1. At hypercholesterolemia absorption of LDLP is activated. That
causes endotheliocytes proliferation and accumulation of LDLP in intimae.
2. Endothelium injury is common uncontrolled penetration of LDLP inside the vessel wall.
3. On endothelium surface is activated lipoprotein lipase, which controls dissociation of VLDLP into LDLP and HDLP
1 STAGE –
“FOAM CELLS”
Role of the smooth muscle cellsDeposit of LDLP in intimae causes excretion of
hemotaxis factors by endotheliocytes, macrophages and fibroblasts. These substances conduce smooth muscle cell (SMC) hemotaxis into intimae (contractile cells have ability to change in secretory).
What do they do ???1. They absorb of LDLP (they have Аpо-В and Аpо-Е
receptors)2. They proliferate (due to thrombocyte growth factor.
Their DNA synthesis activates and mitosis occurs)3. They synthesize collagen, elastin,
glycoseaminoglucans (connective tissue matrix of plaque)
1 STAGE – “FOAM CELLS”
2 stage – LIPID BLOTS
They are formed on different parts of
arterial system (in elastic and elastic-muscle type of vessels):
They have different square in different age:
in aorta – 10 % in 10,
30-50% in 25-30
in coronary arteries –
appear in 15
in cerebral arteries –
appear in 35-45
There is proved that this stage can be reversible due to prolonged uncholesterol diet
Formation mechanismFoam cells overload by
cholesterol causes their damage. At this time hydrolytic lisosomal enzymes release, which causes necrosis of surround tissue.
2 stage – LIPID BLOTS
Contents of LIPID BLOTS:
- Foam cells
- Моnocytes/macrophages
- Smooth muscle cells
- Lymphocytes
- Free cholesterol
- Connective tissue
Main characteristic – don’t violate blood flow
3 stage – FIBROUS PLAQUE
Cholesterol and lisosomal enzymes
irritates intimae (because they are the alien bodies)
Excreation of proliferation factors by macrophages, еndotheliocytes, lymphocytes, thrombocytes
SMC migration in intimae and active proliferation collagen and elastin (capsule for Cholesterol and injured vessel wall isolation)
3 stage – FIBROUS PLAQUE
Fibrous plaque. Adhesion of lymphocytes on endothelium, which covers plaque. Electron microscopy (magnific.3500)
characteristic- Contents: ЕChol, NEChol,
oddments of elastin and collagen, foam cells, Chol crystals, necrotical mass
- Vessel narrowing
- Stage unalterable- Partial regression
(dilipidation) at diet without Chol (150-160mg/dl) during 1,5-2 years
3 stage – FIBROUS PLAQUE
1. tHROMBOSIS (due to endotheluum
damage)
2. Ulceration(necrosis of and
releasing of lisosomal enzymes causes damage of plaque wall)
3. Calcinations(deposit of insoluble
calcium salts)
4 stage - COMPLICATIONS