Disorder of lipoprotein metabolism. Atherosclerosis

Ph.D., MD, Assistant ProfessorBakalets O.V.

Atherosclerosis is the human’s payment

for long life

“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

Scheme of the receptor-mediated mechanism LP transportinside the cell

Аpоprotein-В

Scheme of LDLP structure

PhL

Non-aether Ch Ch aethers

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. Hypercholesterolemia2. Dislipoproteinemiaа) 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 endotheliocytes3. Retention of LDLP damage by free radicals4. Increase prostacycline synthesis and and as a result

decrease thrombocytes aggregation5. Decrease proliferation of the smooth muscle cells, which is

induced by LDLP6. 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

4 stage - COMPLICATIONS