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Biomedical subjects

A N Orekhov

Publications and source records attributed to A N Orekhov.

At least 145 records · Page 8Linked to original sources
PubMed1988

Stable analogues of prostacyclin and thromboxane A2 display contradictory influences on atherosclerotic properties of cells cultured from human aorta. The effect of calcium antagonists.

We examined the influence of stable prostacyclin analogues (carbacyclin) and thromboxane A2 (U46619) on atherosclerotic properties of cells: [3H]thymidine incorporation and intracellular cholesterol content. A primary culture of human aortic subendothelial cells derived from atherosclerotic plaques was used. Carbacyclin exerted a direct anti-atherosclerotic effect, significantly reducing atherosclerotic manifestations of cells, while agent U46619 stimulated proliferation and cholesterol accumulation, i.e. demonstrated atherogenic potency in culture. Calcium antagonists (verapamil and diltiazem) markedly enhanced anti-atherosclerotic properties of carbacyclin and restricted the atherogenicity of U46619.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Intracellular cholesterol accumulation is accompanied by enhanced proliferative activity of human aortic intimal cells.

Cholesterol accumulation in smooth muscle cells of unaffected human aortic intimal tissue occurred in the following conditions: (1) incubation of cells with atherogenic blood serum from patients with coronary heart disease (CHD), (2) cultivation of cells in the presence of insoluble associates containing low density lipoprotein (LDL). Preincubation of cells with blood serum from CHD patients resulted in a 2-5-fold increase in intracellular cholesterol and in 1.5-3-fold increase in cellular [3H]thymidine uptake. Blood serum collected from healthy donors had no significant effect on cultivated smooth muscle cells. When intimal cells were preincubated with insoluble associates containing LDL and components of fibrous extracellular matrix, the level of intracellular cholesterol increased from 2-4 times and uptake of [3H]thymidine increased 1.5-2.5-fold. Thus, a strong correlation was found between [3H]thymidine incorporation and intracellular cholesterol accumulation. The current study suggests that intracellular lipid accumulation may stimulate the proliferative activity of human aortic intimal cells from uninvolved tissue.

Aorta↗
PubMed1988

Modulation of human aorta smooth muscle cell phenotype: a study of muscle-specific variants of vinculin, caldesmon, and actin expression.

Vinculin- and caldesmon-immunoreactive forms and actin isoform patterns were studied in samples of normal and atherosclerotic human aorta. After removal of adventitia and endothelium, the remaining tissue was divided into three layers: media, muscular-elastic (adjacent to media) intima, and subendothelial (juxtaluminal) intima. In media of normal aorta, meta-vinculin accounted for 41.0 +/- 0.9% (mean +/- SEM) of total immunoreactive vinculin (meta-vinculin + vinculin); 150-kDa caldesmon accounted for 78.2 +/- 5.1% of immunoreactive caldesmon (150-kDa + 70-kDa); the fractional contents of alpha-smooth muscle actin, beta-nonmuscle, and gamma-isoactins were 49.0 +/- 0.6%, 30.4 +/- 0.6%, and 20.8 +/- 0.8%, respectively. Muscular-elastic intima was very similar to media by these criteria. In subendothelial intima, the fractional content of meta-vinculin and 150-kDa caldesmon was significantly lower (6.9 +/- 1.5% and 32.7 +/- 7.0%, respectively) than in muscular-elastic intima and media, whereas the isoactin pattern was identical to that in adjacent layers, demonstrating the smooth muscle origin of subendothelial intima cells. In atherosclerotic fibrous plaque, the fractional content of alpha-actin was decreased in subendothelial intima, rather than in media and muscular-elastic intima. Additionally, the proportion of subendothelial intima cells [i.e., the cells that express low amounts of smooth muscle phenotype markers (meta-vinculin, 150-kDa caldesmon, and alpha-actin)] in the total intima cell population increased dramatically in atherosclerotic fibrous plaque. The results suggest that changes in the relative content of meta-vinculin and 150-kDa caldesmon as well as alpha-actin in human aortic intima are associated with atherosclerosis although, in subendothelial intima of normal aorta, a certain smooth muscle cell population exists that expresses reduced amounts of "contractile" phenotype markers, even in the absence of the disease.

Actins↗
PubMed1988

Blood serum atherogenicity associated with coronary atherosclerosis. Evidence for nonlipid factor providing atherogenicity of low-density lipoproteins and an approach to its elimination.

To reveal the presence of atherogenic potential in the blood serum obtained from patients with angiographically assessed coronary atherosclerosis we used primary cultures of subendothelial cells isolated by collagenase from unaffected human aortic intima. Earlier, we have demonstrated that such cultures are made up mostly of typical and modified smooth muscle cells. Within 24 hours of cultivation with a 40% sera of patients suffering from coronary atherosclerosis, the total intracellular cholesterol level increased twofold to fivefold. Cultivation with the sera of healthy subjects had no effect on the intracellular cholesterol level. The sera of patients were separated by ultracentrifugation into two fractions: total lipoprotein fraction containing the main classes of lipoproteins and a lipoprotein-deficient fraction. The former, but not the lipoprotein-deficient fraction, was characterized by atherogenicity (i.e., the ability to induce the accumulation of intracellular cholesterol). Lipoproteins of the patients' serum were separated into main classes: low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL2 and HDL3). An atherogenic component of the serum capable of stimulating the deposition of intracellular cholesterol was represented by LDL and, in one case, by VLDL, but not by other classes of lipoproteins. LDL and other lipoproteins isolated from the blood serum of healthy subjects failed to raise the cholesterol content in cultured cells; that is, they were nonatherogenic.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1988

Cardiovascular drugs and atherosclerosis: effects of calcium antagonists, beta-blockers, and nitrates on atherosclerotic characteristics of human aortic cells.

Primary cell culture derived from atherosclerotic plaque of human aorta was used to assess direct effects of calcium antagonists, beta-blockers, and nitrates on vessel wall cells. Within 24 h, calcium antagonists (verapamil, nifedipine, darodipine, isradipine, diltiazem, etc.) reduced the cholesterol level in cultured cells. Furthermore, these agents decreased the incorporation of [3H]thymidine. Thus, the calcium antagonists manifested direct antiatherosclerotic action in culture by normalizing major manifestations of atherosclerosis at the cellular level. On the other hand, beta-blockers (propranolol, alprenolol, metoprolol, atenolol, pindolol, and timolol) caused a 1.5- to twofold rise in cholesterol level of cultured cells and stimulated their proliferation. Nitrates (nitroglycerin, isosorbide dinitrate, and nitroprusside) had no effect on atherosclerotic characteristics. Within 2-4 h after a single dose of oral administration of beta-blocker (propranolol), patients' blood plasma turned atherogenic, i.e., its addition to culture-induced cholesterol accumulation and stimulated proliferation. At the same time, blood plasma of patients who received calcium antagonists (verapamil and nifedipine) acquired antiatherosclerotic properties manifested in its ability to lower the intracellular cholesterol level and inhibit proliferative activity of cultured cells. These findings allow the assumption that not only in vitro, but in vivo as well, calcium antagonists and beta-blockers are antiatherosclerotic and atherogenic drugs, respectively.

Adrenergic beta-Antagonists↗
PubMed1988

Prostacyclin, thromboxane A2 and calcium antagonists: effects on atherosclerotic characteristics of vascular cells.

We investigated the effects of stable analogues of prostacyclin (carbacyclin) and thromboxane A2 (U46619) and various calcium antagonists on atherosclerotic cellular indices, intracellular cholesterol content and [3H]thymidine incorporation. Primary culture of human subendothelial cells derived from atherosclerotic plaques of aorta was used. Carbacyclin reduced cholesterol accumulation and cell proliferation. U46619 in opposite to carbacyclin stimulated this processes. In general, carbacyclin exerted a direct antiatherosclerotic and U46619 - atherogenic action in culture. Calcium antagonists: dihydropyridines, verapamil derivatives and diltiazem demonstrated antiatherosclerotic properties themselves and potentiated carbacyclin effect but restricted atherogenicity of U46619.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

The effects of eicozanoids and lipoxygenase inhibitors on the lipid metabolism of aortic cells.

The influence of stable analogues of prostacyclin (carbacyclin) and thromboxane A2 (U46619), as well as lipoxygenase inhibitors, on the lipid metabolism of cells cultured from atherosclerotic intima of human aorta was analyzed. Carbacyclin and at concentrations of 200 ng/ml during 24 hours of incubation caused a 2-fold decrease in the level of cholesteryl esters and triglycerides in cells obtained from atherosclerotic lesion. Phospholipid and free cholesterol content did not change during the same period. Carbacylin decreased incorporation of [14C]oleate into intracellular neutral lipids. U46619 produced intracellular lipid accumulation. U46619 stimulated uptake [14C]oleate into triglycerides and cholesteryl esters. Two lipoxygenase inhibitors possessed "antiatherosclerotic" activity in primary culture significantly reducing cholesteryl ester content of cells isolated from atherosclerotic lesions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

[Effect of lipostabil on cholesterol levels in atherosclerotic plaques of the human aorta and the aggregative capacity of thrombocytes (in vitro study)].

It was found out that lipostabil induced decrease in cholesterol contents in both organ and primary culture of human aorta atherosclerotic plaques. This phenomenon was caused by the effect of lipostabil on cellular output of cholesterol. The study of concentration dependence showed that the cholesterol-decreasing effect of lipostabil was maximal at its concentration in the medium over 250 microliter/ml. At such concentration lipostabil had no significant effect on the blood rheology and inhibited to a great extent platelet aggregation induced by phospholipid platelet activating factor and by some other agents.

Anticholesteremic Agents↗
PubMed1987

The gangliosides of adult human aorta: intima, media and plaque.

The composition, structure and localization of gangliosides of aorta taken from subjects who had died after myocardial infarction were studied. Individual gangliosides were purified by high-performance liquid chromatography and high-performance thin-layer chromatography and were characterized on the basis of their chromatographic mobility, carbohydrate composition, neuraminidase hydrolysis and methylation analysis. The main aortic gangliosides were identified as GM3, GM1, GD3, GD1a and GT1b. Significant differences in the ganglioside composition of intima and media were detected and the ganglioside profile of atherosclerotic plaques was found to differ markedly from that of unaffected intima. The latter was characterized by high content of GD3, a ganglioside thought to be associated with membrane permeability, cell interaction, adhesiveness and growth and to suppress unspecific immune responses. Possible implications of the results in low-density lipoprotein binding to the arterial wall and in immunological changes induced by atherosclerotic lesions are discussed.

Adult↗
PubMed1987

Association of low-density lipoprotein with particulate connective tissue matrix components enhances cholesterol accumulation in cultured subendothelial cells of human aorta.

Low-density lipoproteins (LDL) were incubated with elastin particles, collagenase-resistant debris isolated from human aorta, and latex beads of 1.13 microns in diameter. As a result of incubation, insoluble LDL-associates were formed. These associates, as well as LDL-heparin-fibronectin-gelatin complexes described by other workers, were added to a 7-day primary culture of enzyme-isolated cells of human aortic subendothelial intima. The culture contained a mixed cell population made up mostly of typical and modified smooth muscle cells. 24 h later, total cholesterol, phospholipid, triacylglycerol, free cholesterol and cholesteryl ester levels were measured. Addition of insoluble LDL-complexes as well as LDL-associates to culture brought about a substantial accumulation of intracellular lipids; primarily, cholesteryl esters. The total cholesterol level in cultured cells was raised 3- to 8-fold. Addition of free LDL or LDL-free particles had no effect on the content of intracellular lipids. The results obtained allow the assumption that the occurrence of the LDL-mediated accumulation of intracellular lipids is due mainly to the LDL penetration inside the cell via 'nonspecific' phagocytosis and not through a regulated receptor-dependent pathway.

Adult↗
PubMed1987

Cyclic nucleotides and atherosclerosis: studies in primary culture of human aortic cells.

A primary culture of cells derived from uninvolved and atherosclerotic intima of human aorta was used to elucidate the role of cyclic nucleotides in atherogenesis. The cells cultured from fatty streaks and atherosclerotic plaques had a 2- to 8-fold lower cyclic AMP level and a 1.5- to 2-fold higher level of cyclic GMP compared with those of a grossly normal intima. Medial cells cultured from nonlesioned and atherosclerotic aortic segments showed no differences in the cyclic nucleotide concentrations. Reduction of the intracellular cyclic AMP with 2'-deoxyadenosine or a cyclic GMP elevation with its dibutyryl derivative, or liposomes containing cyclic GMP stimulated the uptake of [3H]thymidine and protein synthesis in the cells cultured from unaffected intima. On the contrary, a rise of the intracellular cyclic AMP caused by adenylate cyclase activators, a phosphodiesterase inhibitor, dibutyryl cyclic AMP, and liposomes containing cyclic AMP inhibited cell proliferation and protein synthesis. Elevation of the intracellular cyclic AMP stimulated the hydrolysis of lipids which led to reduction of lipid levels in the cells cultured from atherosclerotic lesions. The results of this study corroborate the existence of a relationship between the alterations of intracellular cyclic nucleotide levels and the metabolic disorders occurring in atherosclerosis.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Disorders in the system of cyclic nucleotides in atherosclerosis: cyclic AMP and cyclic GMP content and activity of related enzymes in human aorta.

Cyclic AMP and cyclic GMP content and activities of cyclic nucleotide metabolic enzymes were determined in intima and media of atherosclerotic and unaffected human aorta obtained shortly after death due to myocardial infarction. Cyclic AMP content in fatty streaks and atherosclerotic plaques was lower by three- and five-fold, respectively, as compared with uninvolved intima. Cyclic GMP level in atherosclerotic lesions was estimated to be three-fold higher than in grossly normal area. Basal activity of adenylate cyclase in fatty streaks and plaques was two- to six-fold lower than in unaffected intima. Besides, the ability of adenylate cyclase to be stimulated by the stable analogue of prostacyclin, carbacyclin, was suppressed in plaques. Guanylate cyclase activity in fatty streaks was 1.5- to three-fold higher than in normal tissue. The thiol-reducing agent, dithiothreitol, decreased the enzyme activity to normal level, suggesting the oxidative nature of guanylate cyclase activation in the lesion zone. There were no significant changes in cyclic AMP phosphodiestease activity in the regions of the atherosclerotic lesion. Cyclic GMP phosphodiesterase activity in atherosclerotic plaques was two-fold lower than in the intima of unaffected areas. We did not find differences in the content of cyclic nucleotides or related enzyme activities in the media of uninvolved areas of human aorta nor in the media underlying atherosclerotic lesions. Our findings suggest that development of human atherosclerotic lesions is accompanied by dramatic changes in the cyclic nucleotide metabolism featuring gradual hormonal receptor uncoupling from adenylate cyclase, activation of guanylate cyclase in fatty streaks and inhibition of cyclic GMP phosphodiesterase in plaques.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1987

On the role of cyclic nucleotides in the pathogenesis of human atherosclerosis.

The content of cAMP and cGMP was measured in the intima and media of unaffected and atherosclerotic areas of human aorta in a short-term organ and cell cultures. In an organ culture the cAMP content in fatty streaks and atherosclerotic plaques is significantly (2 to 7-fold) lower than in unaffected intima. The cGMP level in atherosclerotic lesions is 1.5 to 3-fold higher than normal. The content of both cyclic nucleotides in the media underlying fatty streaks and plaques is the same as in the normal tissue. Similar alterations of cAMP and cGMP levels were seen in the cells cultured from atherosclerotic lesions. Cholera toxin, methylisobutylxanthine and forskolin as well as dibutyryl cAMP inhibit by 2-7-fold[3H]thymidine uptake into intimal cells cultured from atherosclerotic human aorta. These agents also decrease cholesteryl ester and triglyceride levels and do not affect the content of phospholipids and free cholesterol in the cells cultured from atherosclerotic lesions.

1-Methyl-3-isobutylxanthine↗