Biomedical subjects
Publications and source records attributed to A N Orekhov.
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Preparations of low-density lipoproteins from healthy donor blood contain lipoprotein particles with different capacity for aggregation: upon stirring, some particles form aggregates significantly more quick than others. After stirring, lipoprotein particles are separated by ultracentrifugation into two fractions: a fraction of large aggregates and a fraction of small particles without intermediate forms. It is known that lipoprotein aggregates can accelerate intracellular accumulation of lipids. Therefore, it is supposed that particles of high aggregation ability are more atherogenic.
Different approaches based on the spin probe method were used to compare the physical state of the surface lipid monolayer in subfractions of low-density lipoproteins: in native low-density lipoproteins constituting the bulk of human blood low-density lipoproteins and in circulating multiple-modified low-density lipoproteins whose portion is minor in healthy persons but significantly increases in atherosclerotic patients. The data obtained in in vitro experiments suggest that circulating multiple-modified low-density lipoproteins possess atherogenic properties. The order parameter S, rotational correlation time tau, and hydrophobicity parameter h were calculated from electron spin resonance spectra of a series of spin probes whose paramagnetic groups are located at different depths of the lipid monolayer. These parameters characterize the molecular packing, fluidity, and polarity in the microenvironment of paramagnetic groups. The kinetics of the reduction of paramagnetic groups by ascorbate and oxidation by hypochlorite were obtained for the spin probe whose paramagnetic group is located deeply in the lipid monolayer at the level of the terminal segments of phospholipid acyl chains. No difference between native low-density lipoproteins and circulating multiple-modified low-density lipoproteins was revealed in respect of the physical properties of the lipid domain of surface proteolipid layer, as sampled by spin probes.
Blood serum of 63 persons out of 191 men examined, randomly selected among non-organized population, caused in primary culture of mice peritoneal macrophages the 1.3-4-fold increased accumulation of intercellular cholesterol. Blood serum of other 128 men studied did not exhibit any atherogenic properties in the culture. The atherogenic potential of blood serum did not correlate with content of blood serum lipids, apolipoproteins B and A-I, while it correlated with the ratio apo B/apo A-I in blood serum and with one of ischemic heart disease risk factors--increased arterial pressure. Blood serum atherogenic potential, detected in experimental model, appears to be involved in development of human atherosclerosis.
Consumption of 15 g of 40% eicosapentaenic acid within 3 days resulted in 3-fold increase of its content in blood serum of healthy persons and of patients with heart ischemic disease, whereas concentration of arachidonic acid was unaltered. Administration of blood serum containing increased content of eicosapentaenic acid into cell culture of human aorta intima caused a decrease in accumulation of the intracellular cholesterol and in 3H-thymidine incorporation. Simultaneous addition of the blood serum containing eicosapentaenic acid and the structure derivative of A2 thromboxane V 46619 into the aorta intima cell culture led to a distinct decrease in the atherosclerotic effect of the latter drug. Combination of the blood serum with carbocycline or with prostaglandin I2 resulted in the most pronounced lowering of intracellular cholesterol content and of the cell proliferating activity. The antiatherosclerotic effect of eicosapentaenic acid appears to relate not only to the fact that the drug is precursor of prostaglandine I2 and I3 but also to the regulating effect on a balance of various prostaglandins.
Administration of eicosapentaenic acid (EPA) preparations to patients with type IIb hyperlipoproteinemia brought about a 22-36-percent decrease in blood serum of total cholesterol, triglycerides, beta-lipoproteins, and total lipids. At the same time the administration of EPA preparations was followed by the acquisition of the antiatherosclerotic properties by the patients and healthy donors serum. This could be judged from the reduction of intracellular cholesterol accumulation and intensity of the proliferation of the cells of human aorta intima, inoculated into the culture of the study serum. The data obtained suggest that the antiatherosclerotic properties of the serum are determined to a certain degree by the correlation in it between EPA and arachidonic acid.
Glucagon and concanavalin A were administered into cell cultures of mice peritoneal macrophages and human intima aorta simultaneously with atherogenous blood serum, obtained from patients with ischemic heart disease, or with acetylated and native low density lipo-proteins. Their effect was dissimilar: glucagon decreased accumulation of intracellular cholesterol and the rate of 3H-thymidine incorporation into these cells, while concanavalin A increased the patterns studied. Cellular lysosomes appear to participate in atherogenesis, these results suggest that regulation of lysosomal apparatus may occur at the step of secondary lysosomes formation.
Activity of lysosomal proteinases cathepsins A, B, C, D and L was studied in cultivated cells of human aorta intima, isolated from intact zone of aorta, from lipid stria and atherosclerotic patch. The highest enzymatic activity was detected in the lipid stria cells and the lowest activity - in atherosclerotic patch. Atherogenous blood serum, added simultaneously with pepstatin or leupeptine into the cell culture of intact aorta, caused a distinct increase in the proliferating activity of these cells and in the level of cholesterol accumulation, while activities of cathepsin D or B and L were inhibited by 80-100%, respectively. The data obtained suggest that lysosomal proteolytic system plays an important role in development of atheromatous impairment of vascular wall.
Antiatherosclerotic properties of water and alcoholic extracts of 20 types of high-species mushrooms were investigated by evaluation of intracellular cholesterol accumulation and 3H-thymidine inclusion into the cells of the human aortal intima in culture. The influence of a single intake of some mushroom species on antiatherosclerotic properties of the human sera was studied. It has been shown that Ganoderma lucidum and Lentinus edodes possess pronounced antiatherosclerotic properties.
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Functional and structural properties of fibronectin--high molecular weight glyco-protein from human plasma--were studied by monoclonal antibodies against fibronectin. It was shown that monoclonal antibodies against human plasma fibronectin exhibit a certain species specificity. Antigenic determinant for our monoclonal antibody is located in the central part of the protein polypeptide chain--in the structural domain. The monoclonal antibodies studied do not inhibit any tested functions of fibronectin. In contrast, polyclonal antibodies are not species specific and inhibit all fibronectin functions.
Lipid composition was studied in media and intima of human atherosclerotic aorta as well as in cells from the both layers of the vessel wall. A correlation was found between the content of main lipids in the cells and the tissue, from which these cells were isolated. The lipid composition of cells, isolated from normal and atherosclerotic aorta zones, was unaltered within 12 days of cultivation. Primary culture of human atherosclerotic aorta cells might be used for study of lipoidosis in atherosclerosis.
Blood serum atherogenicity was studied in children suffering from type I diabetes mellitus, as was the relationship between the serum atherogenicity and a number of clinical biochemical parameters. Of the 34 serum samples from children with diabetes 16 did not influence the intracellular cholesterol levels, the rest 18 were found atherogenic, that is, they increased the total cholesterol levels in the cells by 50-70%. Blood serum atherogenicity in all the examinees and in groups A and B separately was unrelated to the patients' age, insulin dose, fructosamine levels, or the disease standing. A positive correlation was detected between the patients' ages and the insulin dose.
The authors have examined the effects of sulfonylurea drugs glibenclamide and glipizide and of their analogs manilil and minidiab on cholesterol levels in murine peritoneal macrophages. Both glibenclamide and glipizide had a direct atherogenic effect on cultured murine peritoneal macrophages. A similar effect was observed in vivo: blood sera of diabetics after a single intake of 5 mg of manilil or minidiab increased the atherogenic potential of cultured murine peritoneal macrophages.
Effects of oral sugar-reducing sulfonylurea drugs, glibenclamide, glypizide, and glyclaside, on intracellular cholesterol level of murine peritoneal macrophages were studied, as were papaverin effects on atherogenicity induced by sulfonylurea derivatives. Direct effect of sulfonylurea preparations and of blood sera from patients with type II diabetes on atherogenic potential after the said drugs intake were studied in cell cultures. All the drugs mentioned increased intracellular cholesterol level by 1.5 times both in vitro and in vivo. Papaverin, if administered simultaneously with sulfonylurea drugs, markedly reduced atherogenic potential induced by these drugs. Addition of papaverin to culture medium containing 10(-4) mole/liter of sulfonylurea drugs resulted in a reliable reduction of their atherogenic effect, the maximal effect being observed at papaverin concentration 10(-5) mole/liter. Hence, papaverin is capable of eliminating an unfavorable atherogenic effect of sulfonylurea drugs.
The task of this research was to study exogenous insulin effect on blood serum atherogenic potential in patients with type I diabetes mellitus. Under study were relationship between blood serum atherogenic potential in diabetics and daily insulin dose and duration of therapy, as well as exogenous insulin effect on the major atherosclerotic manifestations in tissue cultures, such as intracellular cholesterol content in cultured cells and labeled thymidine incorporation in cellular nuclei DNA. Blood serum atherogenicity did not correlate with insulin dose and duration of insulin therapy both in adult patients and children. Insulin prescription to newly detected patients with type I condition did not influence blood serum atherogenic potential. Exogenic insulin did not influence the major atherosclerotic manifestations at the cellular level, namely, on intracellular cholesterol content in cultured cells and these cells proliferative activity; it had no influence on blood serum atherogenic potential of the patients with type I condition.
Study of the effects of squid liver fat and krill meat on blood serum atherogenic characteristics in patients with type I diabetes has shown that these foodstuffs had a certain atherogenic effect, for their consumption was associated with a marked reduction of blood serum atherogenicity. The mechanism of this effect is still to be researched.