1. Disorder of lipoprotein metabolism. Atherosclerosis Ph.D., MD, Assistant Professor Bakalets O.V.

2. Atherosclerosis is the human’s payment for long life

3. “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)

4. First experimental model of atherosclerosis was created on rabbits. Every day within 3- 4 months Annickov added 10 g of Cholesterol in rabbits ration.

5. 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-aether cholesterol phospholipids Cholesterol aethers threeglicerides Apoprotein

6. Kinds of the lipoproteins IndexesChMVLDLP, pre-  -LP LDLP  -LP HDLP  -LP Diameter, nm10025-7519-246-12 Chemical structure (%): Ch general0,5- 315-1735-4820-37 % aeter Ch465766-7078 PhL3-913-2011-3024-40 TG80-9550-705-103-5 Protein1-25-1214-2545-55 ApoproteinsA, B, C, EB, CB, C, EA, C, D, E

7. Аpо-В-receptor Аpо-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 LymphocyteMacrophage

8. Scheme of the receptor-mediated mechanism LP transport inside the cell

9. Аpоprotein-В Scheme of LDLP structure PhL Non-aether Ch Ch aethers

10. Peculiarities Are made - in blood - extracellular space - in arterial wall Modified LDLP Properties 1. 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

11. 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

12. Ch metabolism violation 1. 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

13. 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

14. 1. Male 2. Оbesity 3. Hypokinesia 4. Hyperthreeglyceridemia 5. Using much carbohydrates 6. Diabetes mellitus in adult 7. Genetical defect of Apo- А synthesis 8. Smoking 1. Female 2. Physical activity 3. Low body weight 4. Moderate alcohol use Low level HDLPHigh level HDLP

15. 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

16. 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

17. Figure. “FOAM CELL” macrophage origin, which was getting from aorta intimae of a human. Electron microscopy. Magnify 7000 1 STAGE – “FOAM CELLS”

18. Role of endotheliocytes There is no deposit of LDLP inside the endotheliocytes!!!!!!!!! а) Due to Аpо-В,Е-receptors entrants of LDLP is controlled б) 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”

19. Role of the smooth muscle cells Deposit 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”

20. 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

21. There is proved that this stage can be reversible due to prolonged uncholesterol diet Formation mechanism Foam 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

22. 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)

23. 3 stage – FIBROUS PLAQUE Fibrous plaque. Adhesion of lymphocytes on endothelium, which covers plaque. Electron microscopy (magnific.3500)

24. 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

25. 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