[Effect of prolonged intake of lovastatin on the number of glucocorticoid receptors in peripheral blood lymphocytes].
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Biomedical subjects
Publications and source records attributed to Iu A Shakhov.
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A study was made of adrenocortical function by measuring blood plasma cortisol concentration and amount of glucocorticoid receptors in lymphocytes as well as thyroid function by measuring blood plasma triidothyronine and thyroxine concentration in 58 bronchial asthma children aged 1 to 14 years. The authors revealed alterations in the functional activity of the indicated endocrine glands depending on the intensity of bronchial patency disorders and the nature of the therapeutic measures carried out.
The rate of endogenous cholesterol synthesis in blood lymphocytes and skin fibroblasts from patients with type IIa hyperlipidemia was found to be increased in comparison with healthy donors. The cells of hyperlipidemic patients had lowered levels of glucocorticoid receptors concomitantly with a partial loss of their sensitivity to glucocorticoids. In fibroblasts from patients with hereditary hypercholesteremia of homozygous type the number of glucocorticoid receptors did not exceed 10% of their content in normal cells. The decrease of the number of glucocorticoid receptors in patients with type IIa hyperlipidemia seems to be a compensatory response of cells culminating in activation of endogenous cholesterol synthesis.
HDL-subfraction was studied in blood serum of drinkers after alcohol intake and control group of men-nondrinkers. Blood serum incubation with fibroblasts culture did not indicate principal differences between drinkers and nondrinkers both with normolipemia and hyperalphacholesterolemia. Increase of HDL2 and decrease of HDL3-subfraction were observed. Incubation of the same species with hepatoma cells culture (Hep G-2) demonstrated significant differences between normolipemia and hyperalphacholesterolemia. The reduction of HDL2 subfraction level and increase of HDL3 have been found in nondrinkers with normolipemia. The raise of HDL2 was demonstrated in hyperalphacholesterolemia (due to HDL2b and HDL2a in drinkers and HDL2a in nondrinkers). Besides, in several samples of normolipidemic blood serum taken after alcohol abuse the changes of HDL-subfractions were identical to those receiving in hyperalphacholesterolemia. It is postulated that one of the mechanisms of the alcoholic hyperalphacholesterolemia development is the decline of the transfer rate of cholesterol ethers to the liver and accumulation of HDL2 particles in total HDL pool.
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Number of alpha-2-adrenoceptors on the thrombocyte membranes was measured with selective antagonists [H]3 yohimbine in 25 patients with ischemic heart disease (7 patients with unstable 12 with vasospastic and 6 with new onset angina pectoris) and in 16 patients without ischemic heart disease and coronary atherosclerosis (control group). The number of alpha-2-adrenoceptors in patients with unstable angina pectoris (571.0 +/- 92.9) was proved to exceed significantly that in patients with vasospastic (237.9 +/- 30.0) or new onset angina (126.2 +/- 19.3) and in the control group (200.0 +/- 22.5). The number of adrenoceptors tended to decrease during myocardial ischemia.
Using gradient gel electrophoresis, the interconversions of high density lipoproteins (HDL) upon heating for 24 hours at 37 degrees C of blood sera obtained from dyslipidemic patients, were studied. It was shown that during incubation of normolipidemic, hypercholesterolemic and hyperalphacholesterolemic sera, the portion of large particles of HDL2 subclass (HDL2b) is increased with a simultaneous decrease in the portion of the smallest particles of HDL3 subclass (HDL3b and HDL3c). Contrariwise, in hypertriglyceridemic and hypoalphacholesterolemic sera the portion of the largest HDL2b particles is decreased, while that of middle-sized HDL3a is increased. Hence, hypertriglyceridemia and hypoalphacholesterolemia are not associated with an intensive conversion of small HDL3 particles into large HDL2 ones, which may be the reason for the decreased cholesterol transport function of HDL.
The number of 3H-dexamethasone binding sites in lymphocytes of subjects with hypercholesterolemia (HCS) was found to be decreased as compared to the receptor level in normolipidemic patients (N). In HCS-lymphocytes, the dexamethasone-induced inhibition of 3H-thymidine and 14C-acetate incorporation was less pronounced (by 20% and 22%, respectively) than in control cells, which is suggestive of the decreased sensitivity of HCS-lymphocytes to the hormone. An addition of 5-25% HCS blood sera to human skin fibroblast cultures caused a 10-50% decrease in the number of 3H-dexamethasone binding sites and diminished the Kd values 2-3 times. Lipid-depleted HCS-sera had no effect on the glucocorticoid reception in fibroblasts, whereas very low (VLDL) and low (LDL) density lipoproteins inhibited the 3H-dexamethasone binding to the cells. The most potent inhibiting effect was exerted by VLDL (both N-VLDL and HCS-VLDL). HCS-VLDL were more effective than N-LDL. HCS-HDL and N-HDL did not effect the 3H-dexamethasone binding to fibroblasts. In cells preincubated with VLDL dexamethasone inhibited the incorporation of 3H-thymidine and 14C-acetate less intensively (by 27% and 20%, respectively) than in control fibroblasts. The experimental results are suggestive of a decreased sensitivity of peripheral HCS-cells to glucocorticoids, which may shed some light on the mechanism of hypercholesterolemia realization into coronary heart disease and atherosclerosis.
Variation in insulin and C peptide levels was examined in patients with angina of new onset and chronic coronary heart disease. Insulin secretion was increased in all coronary patients, as compared to the controls, and hormonal response to additional stress was abnormal in postmyocardial infarction patients. It is demonstrated that insulin secretion is already changed at early stages of coronary disease, and the pattern of change is presented.
A survey of boys with hypercholesterolemia, hypertriglyceridemia, hypo-alpha-cholesterolemia, a combination of hypo-alpha-cholesterolemia and hypertriglyceridemia, and hyperalphacholesterolemia, and control subjects from two Moscow districts demonstrated significantly elevated plasma testosterone and estradiol values in boys with hypo-alphacholesterolemia. Increased estradiol was also found in boys with hypercholesterolemia and hyperalphacholesterolemia. An inverse relationship between plasma testosterone level and high density lipoprotein (HDLP) cholesterol, and a direct relationship between the estradiol/testosterone ratio and HDLP cholesterol were established. Individuals with high testosterone and estradiol levels had elevated systolic arterial BP, and those with high systolic arterial BP showed increased testosterone and estradiol levels. It is suggested that reduced high density lipoprotein cholesterol and elevated systolic arterial BP in boys with increased testosterone levels may be regarded as early signs of developing hypo-alphacholesterolemia in combination with arterial hypertension.
Using gradient gel electrophoresis, the dynamics of subfractional spectrum of high density lipoproteins (HDL) according to the particle size was studied during HDL interaction with hepatoma Hep-G2 cells and human skin fibroblasts. It was found that incubation of sera obtained from normolipidemic donors with cholesterol-loaded fibroblasts results in a decrease of the proportion of all small-sized particles of the HDL3 subclass, i.e., HDL3a, HDL3b and HDL3c as well as in an increase in the proportion of large-sized particles of the HDL2 subclass (HDL2a and HDL2b) due to cholesterol acceptance by HDL. In contrast, incubation of the same sera with hepatoma Hep-G2 cells causes a decrease in the proportion of HDL2b and a release of smaller cholesterol-deficient HDL3a particles. The dynamics of subfractional spectrum of HDL in hypoalphacholesterolemic sera is somewhat different, i.e., incubation with fibroblasts results in a decrease of the proportion of HDL3b and HDL3c; that of HDL2a is increased. The HDL2b fraction is unchanged. After incubation of the same sera with hepatoma Hep-G2 cells, the proportion of HDL2b does not fall as in the case of normolipidemic sera, but shows a marked increase. It is concluded that hypoalphacholesterolemia is characterized not only by a low HDL level in the plasma, but also by the formation of HDL2b-deficient particles which less effectively interact with liver cells.
Low (LDL) and high density lipoproteins (HDL) stimulated prostacycline (PGI2) synthesis in rabbit and human aorta smooth muscle cells growing in culture. The lipoproteins were added to the cells in concentrations equal to that of cholesterol. It was shown that HDL exerted a stronger stimulating effect as compared to LDL. The maximal effect was observed with HDL3. HDL3 isolated from blood serum of healthy volunteers appeared to be more active in PGI2 synthesis promotion than those of CDH patients with documented coronary atherosclerosis. Purified Apo A-1 stimulated the transformation of [14C]arachidonic acid into the products of its metabolism with increased accumulation of 6-keto-PGF1 alpha among labeled metabolites. Estradiol (1.10(-7) M) showed a stimulating effect; norepinephrine (1.10(-6) M) and progesterone (1.10(-7) M) showed an inhibiting effect, whereas corticosterone (1.10(-6) M) and deoxycorticosterone (1.10(-6) M) did not influence the rate of LDL-dependent PGI2 synthesis.
Prostaglandins I2(PGI2) and E1(PGE1) (5 X 10(-7) M) reduced by 30% the content of intracellular cholesterol in cultured human aorta smooth muscle cells after 24 hrs of incubation in a medium without fetal calf serum. Total HDL, as well as HDL3 and HDL2b fractions stimulated the effect of prostaglandins on the reduction (by 50%) of cholesterol level.
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Using the freezing-thawing procedure, a highly purified preparation of PPase from R. rubrum chromatophore membranes was incorporated into soybean phospholipid liposomes. The activity of reconstituted PPase was increased in the presence of the uncoupler, FCCP, and the antibiotics, valinomycin (+KCl) and nigericin (+KCl). Oligomycin did not exert any inhibiting action, while imidodiphosphate and NaF significantly decreased the activity of the PPase incorporated into the liposomes. Preincubation of both PPase and ATPase prior to their incorporation into the liposomes did not affect the activity of the reconstituted enzyme. It was concluded that the PPase from R. rubrum chromatophores when incorporated into the liposomes may function as a proton pump independently of the ATPase.
The effects of lipids on the activity of soluble and membrane-bound pyrophosphatase from beef heart mitochondria were studied. An addition of total mitochondrial lipid, phosphatidyl choline, phosphatidyl ethanolamine or cardiolipin resulted in stimulation of the enzymatic activity and an increase in thermal stability of the soluble enzyme. The maximal activating effect was exerted by the total mitochondrial lipid and phosphatidyl choline. The electrophoretic data suggest that phosphatidyl choline is a component of membrane pyrophosphatase. Preincubation of the soluble enzyme with phosphatidyl choline converted the enzyme into a membrane form, which is capable to carry out the energy-dependent synthesis of PPi in submitochondrial particles.
A method allowing to obtain two highly purified forms (membrane-bound and soluble ones) of inorganic pyrophosphatase from bovine heart mitochondria is described. Both forms have the isoelectric point of 5.8, pH optimum with Mg2+ at 7--9, are maximally stable at pH 5.8 and absolutely specific to PPi and require Mg2+ or Co2+ for their activity. The soluble pyrophosphatase is also activated by Zn2+. Besides, the two forms differ in their electrophoretic mobilities, affinity for DEAE cellulose and stability in acidic (pH less than 5.8) and alkaline media.