Currently, ischemic heart disease and cerebrovascular diseases cause major damage to the health of the world’s population. Due to the fact that atherosclerosis is the main cause of coronary heart disease and cerebrovascular disease, its diagnosis, treatment and prevention are very important.
Atherosclerosis is a variable combination of intimal changes of the arteries (unlike arterioles), consisting of focal accumulation of lipids, complex carbohydrates, blood and blood substances, fibrous tissue, calcium deposits and associated with changes in media.
All the most significant theories and hypotheses of the pathogenesis of atherosclerosis fit into the framework of two concepts. One proceeds from the fact that lipids and some proteins (for example, plasma fibrinogen) lead to the development of atherosclerosis and, thus, the onset of atherosclerosis is “introduced” into the arterial wall of blood.
According to another concept, the primary cause of the development of an atherosclerotic process is changes in the cellular, connective tissue, and other structures of the arterial wall under the influence of various factors.
Many leading scientists of the 19th century wrote about imbibition, infiltration and perfusion of lipids as processes leading to changes in the arteries during atherosclerosis. (Virkhov R., Ashoff L., Doerr F.). The same ideas were included in the N. N. Anichkov’s infiltration theory (1915, 1935), according to which a high content of cholesterol in food leads to the development of atherosclerosis. Later, the so-called thrombolipid theory of the pathogenesis of atherosclerosis (Duguid J., 1946; Mustard, 1961) arose , according to which lipids accumulated in the arterial wall somehow “attract” fibrin to themselves, which in turn has the ability to capture lipids. The possibility of lipid drift by platelets lingering between fibrin filaments on the surface of the vessel was also allowed.
Enough supporters have a theory of damage to the endothelium of the arterial wall, which plays the role of a protective barrier against the development of atherosclerosis. Damage to the endothelium due to exposure to hemodynamic factors, toxins, blood clots and other causes contributes to the penetration of macromolecular compounds from the blood plasma into the arterial wall and only in the places of its damage. This was also understood by N. N. Anichkov, who later supplemented the infiltration theory of pathogenesis with a new theory called infiltration-combination, which took into account the state of the vascular wall, the presence of hypertension and other factors.
Peroxide theory gives a certain value to lipid peroxides, which are formed as a result of free radical oxidation of unsaturated fatty acid in the ß-position of the phospholipid component of lipoproteins, as well as the resulting cholesterol hydroperoxide. It is assumed that the penetration of lipoproteins containing oxidized phospholipid acyls and cholesterol hydroperoxides into the vessel wall or the formation of lipid peroxides in the wall itself can cause primary intima damage and intensify the atherosclerotic process.
The American scientist E. Benditt (1974) proposed a monoclonal theory, according to which atherosclerotic lesions can be considered as a benignly growing tumor, the formation of which is caused by viruses or environmental chemicals.
According to the “membrane” theory (Jackson R., Gutto A., 1976), cholesterol esters, in contrast to its unesterified form, are not included in the phospholipid bilayer of the membrane and can be considered as a protective form of excess cholesterol for the cell. If the ability of the cell to synthesize fatty acids and esterify cholesterol is exhausted, then the proliferation of smooth muscle cells begins, in order to utilize the excess cholesterol to build the membranes of newly formed cells.
According to the autoimmune theory of pathogenesis of atherosclerosis, developed by A. N. Klimov et al. (1980, 1985, 1987, 1995), the launch of the atherosclerotic process is caused not so much by lipoproteins as by autoimmune complexes containing lipoproteins as an antigen. Such autoimmune complexes are characterized by a number of features. They cause damage to the endothelium and thereby accelerate the penetration of lipoproteins into the vascular wall; prolong the circulation of lipoproteins in the blood and delay the oxidation and excretion of cholesterol with bile; have a cytotoxic effect, postponing and fixing in the wall of the arteries. There is also a viral hypothesis of the origin of atherosclerosis (Epstein-Barr virus).
The main lipids of human blood plasma are triglycerides, phospholipids, cholesterol esters. These are esters of long-chain fatty acids that are part of lipoproteins and are also present in plasma in free (unesterified) form. The fatty acid depot serves as fatty tissue; their utilization occurs in the liver and muscles, where they are transported in the form of free fatty acids. Triglycerides are esters of fatty acids and glycerol. In the liver and adipose tissue, triglycerides are synthesized via the glycerophosphate pathway, and in the small intestine through the direct esterification of monoglycerides absorbed from food. The so-called endogenous triglycerides are also formed in the small intestine, but their main source is the liver, from where they are secreted in the form of very low density lipoproteins (VLDL).
Cholesterol is a sterol containing a steroid core of four rings and a hydroxyl group. Free cholesterol is a component of all cell membranes, the main form of cholesterol in most tissues. The early stage of cholesterol synthesis is the conversion of acetate to coated acid. The enzyme that determines the rate of this process is 3-hydroxy-3-methylglutorate-coenzyme A-reductase (HMG-CoA reductase), works on the feedback principle. Bile acids – the major metabolites of cholesterol – are synthesized in the liver.
In the body there are three pools of cholesterol. The rapidly exchanging pool is represented by cholesterol from plasma lipoproteins, erythrocytes, liver, intestines and some other organs and contains 20-25 g of pure cholesterol. The intermediate pool includes peripheral tissue cholesterol (skin and fatty tissue), contains about 10-12 g. The greatest amount of cholesterol is in the slowly exchanging pool (skeletal muscles and vessel walls) – 35-37 g. Regardless of the amount of cholesterol that comes from food 35-40% absorbed on average. Normally, the level of total cholesterol in blood plasma varies from 4 to 6.5 mmol / l, however, unlike the level of triglycerides, it does not increase dramatically after the consumption of fatty foods.
All lipids (except free fatty acids) enter the plasma in the form of macromolecular complexes called apoproteins. These complexes contain specific protein components – apolipoproteins (apoproteins or simply apo), interacting with phospholipids and free cholesterol and forming a polar outer shell, shielding non-polar triglycerides and cholesterol esters located inside.
Apolipoproteins perform the following functions:
- interacting with phospholipids, help to solubilize cholesterol esters and triglycerides;
- regulate the reaction of lipids and lipoproteins with enzymes such as lipoprotein lipase and hepatic lipase;
- they bind to receptors on the cell surface, determining the sites of capture and the rate of degradation of other components, in particular cholesterol.
Apolipoproteins A (apo AI and apo AII) are the main protein components of high-density lipoprotein (HDL). Apoprotein B (apo B) differs in heterogeneity and molecular weight. So, apo B100 is found in chylomicrons, VLDL and low density lipoproteins (LDL); apo B48 – only in chylomicrons. Three individual apoproteins belong to apoprotein C and are the main components of VLDL and the minor component of HDL. Apoprotein E enters the plasma mainly in the composition of newly synthesized HDL. In addition, apo D, apo AI-V, apo (a) are isolated.
In connection with various participation in atherogenesis, various classes of lipoproteins are isolated. Chylomicrons are the largest lipoproteins (diameter from 100 to 1000 nm) and contain mainly triglycerides. Their main function is the transfer of food triglycerides from the intestine, where they are absorbed, into the bloodstream. VLDL (pre-ß-lipoproteins) are similar in composition to chylomicrons, but smaller sizes (from 25 to 100 nm), contain less triglycerides, but more cholesterol, phospholipids and protein. VLDL are formed mainly in the liver and serve to transfer endogenous triglycerides. LDL (ß-lipoproteins) is a class of plasma lipoproteins that carry cholesterol.
They differ from VLDL in significantly lower triglycerides and in the presence of only one apo B100 from a variety of apolipoproteins found in VLDL. HDL (a-lipoproteins) by density are divided into HDL2 and LPVPZ. More than 90% of HDL protein is represented by apo A. HDL is synthesized in the liver and small intestine. They play a leading role in the removal of tissue cholesterol. Apo (a) is larger than LDL, but in comparison with them it is more dense and have electrophoretic mobility characteristic of VLDL.
The study of LDL receptors and genetically determined changes in their functioning due to gene mutation allowed us to isolate hereditary forms of dyslipidemia. And if at heterozygous forms the number of LDL receptors decreases, then at homozygous they are completely absent. Today, not only gene disorders associated with a defect in LDL receptors are known, but also mutations of the genes encoding apo-proteins. The transportation of lipids depends on apo-proteins, they change during atherosclerosis.