Ph.D. , MD , Assistant Professor Bakalets O.V.

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

2. Atherosclerosisis the human’s payment for long life

3. “Atherosclerosisis imposible without cholesterol”. А.N.Аnichkov’sconception, 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 ofCholesterolin rabbits ration.

5. non-aether cholesterol phospholipids Cholesterol aethers threeglicerides Apoprotein 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)

6. 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 % aeterCh 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

7. Skin fibroblast Lymphocyte Macrophage Smooth muscles cell Role of LP in Cholesterol transport inside the cell. That is due to receptor-mediated mechanism.It was discovered byAmericanscientists M.Brown and J.Goldsteinin 1973-1975 Brown and Goldsteinhad got Nobel bonus into 1985 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)

8. Scheme of the receptor-mediated mechanism LP transportinside the cell

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

10. Modified LDLP Properties 1. They do not interact with аpоВ- and аpоЕ-receptors 2. Theyinteract with “scavenger ” – receptors. Entrance of LDLP inside the cell results from concentration difference (uncontrolled еndocytosis) Peculiarities Are made - in blood - extracellular space - in arterial wall LDLP changed by free radicals LDLP+Glucose LDLP+Ig LDLP+glucoseaminoglycane

11. LDLP+Glucose aremadein 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 Increase endothelyocytes permeability Conduce blood cells adhesion on endothelyocytes Stimulatemacrophage haemotaxis into arterial wall Stimulatesmooth muscle cells proliferation Stimulateof Ig synthesis and autoimmune damage of arteries

12. ЕТHIOLOGY Endothelium damage 1. Hemodynamic factors а) Local pressure on endotheliocytesleads totheir displacement and damage b) Turbulent motion of the blood (arch of aorta, embranchment of arteries) 2. Immune complexes Ch metabolism violation 1. Hypercholesterolemia 2. Dislipoproteinemia а) LDLP concentration b) Kch = LDLP+VLDLP HDLP (high coefficient correlates to higher probabilityof atherosclerosis)

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 LDLPinside endotheliocytes 3. Retention of LDLP damage by free radicals 4. Increase prostacycline synthesis and and as a result decrease thrombocytes aggregation 5. Decreaseproliferation of the smooth muscle cells, which is induced by LDLP 6. Decreasesynthesis of glucoseaminoglycane by smooth muscle cells

14. Lowlevel HDLP Highlevel HDLP 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

15. 1 STAGE – “FOAM CELLS” PATHOGENESIS Macrophages play main role: • 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. 1 STAGE – “FOAM CELLS” macrophage Scavenger receptor foam cell Decrease LDLP concentration in intimae Migration of macrophage in intimae Migration of macrophage in intimae Many macrophages change into “foam cells”

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

18. 1 STAGE – “FOAM CELLS” Role of endotheliocytes There is no deposit of LDLP inside the endotheliocytes!!!!!!!!! а) Due to Аpо-В,Е-receptors entrantsof LDLP is controlled б) Using of scavenger receptorsstimulates 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

19. 1 STAGE – “FOAM CELLS” 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. Theyproliferate (due to thrombocyte growth factor. Their DNA synthesis activates and mitosis occurs) 3. Theysynthesize collagen, elastin, glycoseaminoglucans (connective tissue matrix of plaque)

20. 2 stage – LIPID BLOTS • They are formed on differentparts 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 – • appearin 15 • in cerebral arteries – • appearin 35-45

21. 2 stage – LIPID BLOTS Main characteristic – don’t violate blood flow Formation mechanism Foam cells overload by cholesterol causes their damage. At this time hydrolytic lisosomal enzymes release, which causes necrosis of surround tissue. Contents of LIPID BLOTS: - Foam cells - Моnocytes/macrophages - Smooth muscle cells - Lymphocytes - Free cholesterol - Connective tissue There is proved that this stage can be reversible due to prolonged uncholesterol diet

22. 3 stage – FIBROUS PLAQUE Cholesterol and lisosomal enzymes irritatesintimae (because they are the alien bodies) Excreation of proliferation factors by macrophages, еndotheliocytes, lymphocytes, thrombocytes SMC migrationin intimaeand 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. 3 stage – FIBROUS PLAQUE 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

25. 4 stage - COMPLICATIONS • 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)

26. 4 stage - COMPLICATIONS