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Biomedical subjects

M Auclair

Publications and source records attributed to M Auclair.

14 recordsLinked to original sources
PubMed1992

Lipophilic beta-blockers inhibit monocyte and endothelial cell-mediated modification of low density lipoproteins.

The effects of propranolol, pindolol and metoprolol on the modification of low density lipoprotein (LDL) by U937 monocyte-like cells, endothelial cells and copper ions were studied by determination of the lipid peroxidation product content and measurement of the relative electrophoretic mobility of the particle. Propranolol and pindolol inhibited LDL oxidation by U937 cells in a dose-dependent manner from 10 to 100 microM, whereas metoprolol had no effect. In the case of LDL modification by endothelial cells, all the three beta-blockers were efficient within the same range of concentrations, and the order of potency was propranolol greater than pindolol greater than metoprolol. In vitro oxidation of LDL in the presence of copper ions was also inhibited by propranolol; pindolol and metoprolol had no significant protective effect in this system. These results concerning the inhibitory action of beta-blockers were confirmed by testing the degradation of modified LDL by J774 macrophages. Although the concentrations of the drugs utilized in this study are relatively high, in long-term treatment beta-blockers might accumulate in target tissues, and the protective effect of propranolol against LDL oxidation might be involved in its inhibitory action on atherosclerosis previously reported in animal models.

Adrenergic beta-Antagonists↗
PubMed1992

Malondialdehyde modification and copper-induced autooxidation of high-density lipoprotein decrease cholesterol efflux from human cultured fibroblasts.

Malondialdehyde modification and copper ion-induced autooxidation of the apo E-free HDL3 fraction of high-density lipoproteins were studied with respect to physico-chemical characteristics and physiological properties of the lipoprotein. Cu(2+)-oxidized HDL was much less modified than MDA-treated HDL, in terms of electrophoretic mobility, lipid peroxidation product content, Lys and Trp amino acid residue level and polymerization of apo A-I. With [3H]cholesteryl linoleate-labeled LDL, an inhibition of cholesterol efflux was observed in the presence of modified HDL, with a more marked effect with MDA-modified HDL. Competition studies with iodinated native HDL demonstrated a decreased binding of modified HDL to cell surface receptors. The decrease in cholesterol intracellular content, determined either by the isotopic equilibrium method or by the enzymatic cholesterol oxidase technic, was less marked in the presence of modified HDL than in the presence of native HDL. MDA-modified HDL was the less effective in decreasing cellular cholesterol content. It is thus suggested that malondialdehyde-induced alteration of HDL, or HDL peroxidation, if occurring in vivo, could contribute to the progress of atherogenesis by decreasing cholesterol efflux from peripheral tissues.

Biological Transport↗
PubMed1991

The liver metabolite S-422 of the hypolipidaemic drug benfluorex decreases cholesterol esterification in fibroblasts and monocyte-like cells.

The effects of S-422 (1-(3-trifluoromethylphenyl)-2-[N-(2-hydroxyethyl) amino] propane), an hepatic metabolite of the hypolipidaemic drug Benfluorex, on lipid metabolism have been investigated in two experimental models: in human fetal lung fibroblasts, for study of the apo B/E receptor-mediated regulation of cholesterol metabolism, and in murine J 774 monocyte-like cells, for study of the scavenger receptor-mediated induction of cholesteryl ester accumulation. In human fibroblasts S-422 increased low density lipoprotein (LDL) catabolism by about 20%, whereas it decreased oleic acid incorporation into triacylglycerols and cholesteryl esters by 25 and 35%, respectively. In J 774 cells, S-422 decreased acetylated LDL degradation and cholesteryl ester formation by about 35%. In both cell types, ACAT activity was significantly reduced by the drug, either after a 24 h pretreatment of the cultured cells, or after an in vitro 30 min preincubation of cell homogenates. The results suggest that S-422, and thus Benfluorex, might prevent the development of atherosclerotic plaques.

Acyl Coenzyme A↗
PubMed1991

Estrogens inhibit copper and cell-mediated modification of low density lipoprotein.

The effects of estrogens on LDL modification by copper ions, U 937 monocyte-like cells or endothelial cells was studied by determination of the lipid peroxidation product content and measurement of the relative electrophoretic mobility. The presence of estradiol, estriol and estrone inhibited LDL oxidation in a dose-dependent manner in the range of concentrations from 5 to 50 microM. In the case of oxidation by Cu2+, the decreasing order of efficiency was: estradiol, estriol, estrone. In monocyte-induced oxidation, the protective effect of estrogens was more marked, and the order of efficiency was the same, except that estrone was as active as estriol. Pretreatment of monocyte cells with estrogens also inhibited the subsequent modification of LDL by these cells, tested in the absence of the hormones. Testosterone had no effect in all the studied systems. Furthermore, the degradation by J774 macrophage like cells of LDL modified either by Cu2+ or monocytes was markedly reduced when modification has been performed in the presence of estrogens. Since oxidative modification of LDL is believed to be involved in the appearance of atherosclerotic plaques, this effect of estrogens might be related to their protective action against atherosclerosis.

Animals↗
PubMed1991

Calcium antagonists prevent monocyte and endothelial cell-induced modification of low density lipoproteins.

Low density lipoprotein (LDL) incubated in the presence of the calcium antagonists verapamil, nifedipine and flunarizine were more resistant than control LDL to human monocyte- or endothelial cell-induced modification, as assessed by electrophoretic mobility in agarose gel, thiobarbituric acid reactive substance content, and degradation by J774 macrophages. The efficiency of the drugs was: flunarizine greater than nifedipine greater than verapamil. Moreover, a 24 h preculture with calcium antagonists significantly impaired the ability of cells to modify LDL in the absence of the drugs. All the studied drugs also inhibited copper-induced autooxidation of LDL. None of the studied calcium antagonists, at concentrations up to 10(-4) M, significantly reacted with free radicals as assessed by the 1,1-diphenyl-2-picrylhydrazyl test. It is suggested that such a protective effect of calcium antagonists against LDL peroxidation could play a role in the previously reported antiatherogenic effect of these drugs.

Animals↗
PubMed1990

Phenothiazines inhibit copper and endothelial cell-induced peroxidation of low density lipoprotein. A comparative study with probucol, butylated hydroxytoluene and vitamin E.

The effect of two phenothiazines, chlorpromazine (CPZ) and trifluoperazine (TFP) on the copper and endothelial cell-induced peroxidation of low density lipoprotein (LDL) has been studied and compared to that of drugs previously shown to protect LDL against peroxidation: probucol (PBC) and butylated hydroxytoluene (BHT). Incubation with CPZ or TFP inhibited in a dose-dependent manner LDL peroxidation induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric reactive substance content of LDL returned to almost normal values in the presence of 50 microM CPZ or TFP. The two studied phenothiazines also strongly inhibited the hydrolysis of LDL phosphatidylcholine which accompanies copper or endothelial cell-induced peroxidation of the particle. CPZ and TFP were as effective as PBC and BHT in inhibiting the LDL peroxidation. Whereas copper or endothelial cell-oxidized LDL were recognized and rapidly catabolized by mouse peritoneal macrophages, CPZ- or TFP-, as well as PBC- or BHT-treated LDL were not. Moreover, it was found that, in contrast to vitamin E, neither CPZ nor PBC reacted with model peroxy radicals formed by gamma irradiation of aerated ethanol. The possible mechanisms underlying this protective effect of phenothiazines against LDL oxidative modification are discussed.

Animals↗
PubMed1990

Verapamil enhances high-density lipoprotein processing in Hep G2 cells preloaded with cholesterol.

The effects of the calcium channel blocker of the arylalkylamine series verapamil have been investigated on high-density lipoprotein (HDL3) catabolism in the human hepatoma cell line Hep G2. It was found that verapamil markedly enhanced HDL3 binding, uptake and degradation in Hep G2 cells preloaded with nonlipoprotein cholesterol. This effect was dose-dependent, and a 1.5-2-fold increase of the three studied parameters was observed in cells pretreated 24 h with 100 microM verapamil. No significant effect of the drug was found in cells not preincubated with cholesterol. Verapamil induced an increase in the cellular cholesterol content in preloaded cells. Other calcium antagonists such as diltiazem, nifedipine, nitrendipine or amphiphilic drugs such as phenothiazines and propranolol also enhanced HDL3 uptake by Hep G2 cells. These effects of verapamil on HDL3 metabolism could be related to its amphiphilic characteristics, and to its calcium antagonist properties.

Calcium Channel Blockers↗
PubMed1990

Modification of phospholipid polar head group with monomethylethanolamine and dimethylethanolamine decreases cholesteryl ester and triacylglycerol synthesis in cultured human fibroblasts.

Modification of the phospholipid polar head group was achieved by supplementation of the growth medium of cultured human fibroblasts with the choline analogues monomethylethanolamine (ME) or dimethylethanolamine (DE) at a concentration of 80-200 micrograms/mL for 48 hr. The maximum concentration of phosphatidylmonomethylethanolamine (PME) or phosphatidyldimethylethanolamine (PDE) reached without affecting the phospholipid/protein ratio was about 45% of total phospholipids. Incorporation of oleic acid into cholesteryl esters and triacylglycerols was markedly inhibited after supplementation with ME or DE, and accounted for 60% and 40% of controls, respectively, at 200 micrograms/mL, whereas incorporation into phospholipids was not affected. AcylCoA:cholesterol acyltransferase (ACAT) and diacylglycerol acyltransferase (DGAT) activities measured on cell-free extracts appeared to be decreased also by phospholipid polar head group modification, whereas the overall phospholipid acyltransferase activity remained unchanged. The intracellular content of cholesteryl esters and triacylglycerols, determined by the isotopic equilibrium method with radioactive cholesterol and glycerol, was found to be diminished to 50-60% and 40-50% of controls, respectively, after supplementation with the choline analogues. The study showed that modification of the phospholipid polar head group affects the activity of membrane-bound enzymes involved in the metabolism of neutral lipids.

Acyltransferases↗
PubMed1990

The antihypertensive drug propranolol enhances LDL catabolism and alters cholesterol metabolism in human cultured fibroblasts.

The effects of 3 beta-blockers with different pharmacological properties (non-selective: propranolol; beta 1-selective: metoprolol; and with intrinsic sympathomimetic activity: pindolol) were comparatively studied on LDL and lipid metabolism in human fibroblasts. At 10(-4) M, propranolol increased low density lipoprotein binding, uptake and degradation by 1.5-, 2.2- and 1.8-fold, respectively, whereas metoprolol and pindolol had no effect. This effect of propranolol is mainly due to an increase in LDL receptor number. Propranolol also enhanced sterol, triacylglycerol, fatty acid and phospholipid synthesis by 2-3-fold from sodium acetate. Cholesterol esterification by oleic acid was significantly and specifically decreased 4-fold by propranolol. Metoprolol and pindolol affect neither sterol synthesis nor cholesterol esterification. Pretreatment of cultured fibroblasts with propranolol induced an increase in hydroxymethyl-glutaryl-coenzyme A reductase activity and a decrease in acyl-coenzyme A: cholesterol-O-acyltransferase (ACAT) activity. Propranolol inhibited the induction of ACAT activity by exogenous cholesterol. Preincubation of a cell-free extract with propranolol also induced inhibition of ACAT activity. Propranolol decreased the cholesteryl ester content of cultured cells. These effects of propranolol on LDL and cholesterol metabolism might be related to the amphiphilic properties of the drug and suggest an effect on the cholesterol intracellular traffic. The decrease in cholesterol esterification and in the cholesteryl ester cellular level induced by propranolol may be involved in its antagonizing effect on experimental atherogenesis.

Cholesterol↗
PubMed1990

Adult sphingomyelinase deficiency: report of 2 patients who initially presented with psychiatric disorders.

We studied 2 unrelated adult patients under neuroleptic treatment who met all phenotypic and biochemical criteria for Niemann-Pick disease type B. In addition, they had chronic psychiatric disorders and low blood levels of HDL cholesterol. The marked and persistent deficiency of acid sphingomyelinase and the disturbance of sphingomyelin metabolism in skin fibroblast subcultures ruled out a pure drug-induced lipidosis. The association of Niemann-Pick disease type B with psychiatric disorders and with low levels of HDL cholesterol could be a chance association of 2 diseases, a new phenotype of Niemann-Pick type B, or the revelation by the neuroleptic treatment of a subclinical inborn sphingomyelinase deficiency.

Adult↗
PubMed1990

[The modification of high density lipoproteins by malondialdehyde changes their interaction with J774 macrophages and decreases cholesterol cell efflux].

The treatment of HDL3 with malondialdehyde (MDA) results in an increase of the electrophoretic mobility of the particle and in aggregation of the apolipoprotein AI. The binding of MDA-treated-HDL3 to murine macrophages J774 is decreased, as compared to native HDL3. The cholesterol efflux is also markedly reduced. In view of the fact that MDA is produced following plaquette aggregation or oxidative stress, the eventual existence of MDA-modified-HOL in vivo might accelerate the appearance of atherosclerotic lesions by reducing cellular cholesterol efflux.

Animals↗
PubMed1989

Carbon disulfide modification and impaired catabolism of low density lipoprotein.

Carbon disulfide interacts in vitro with low density lipoprotein (LDL), resulting in an increased electrophoretic mobility of the particle, due to a decrease in free amino groups of apolipoprotein B-100. The processing of carbon disulfide-modified LDL through the apo B/E receptor pathway of cultured human fibroblasts is decreased as compared to that of native LDL, depending on the level of modification. Carbon disulfide-modified LDL is recognized and degraded by the scavenger pathway of macrophages, but to a lesser extent than acetylated LDL. Carbon disulfide modification decreases the ability of the LDL to down-regulate sterol synthesis and to stimulate cholesterol esterification in fibroblasts. Carbon disulfide-modified LDL markedly stimulates cholesteryl ester formation in macrophages, albeit to a lesser extent than acetylated LDL. These results indicate that after carbon disulfide modification the LDL catabolism is shifted to the scavenger pathway, and are consistent with the fact that carbon disulfide intoxication accelerates the appearance of atherosclerotic lesions.

Amines↗
PubMed1988

Cyclic AMP decreases LDL catabolism and cholesterol synthesis in the human hepatoma cell line HepG2.

A 24h pretreatment of the human hepatoma cell line HepG2 with dibutyryl cyclic AMP in the presence of theophylline induced a dose dependent decrease in low density lipoprotein binding, uptake and degradation. This effect is most likely due to a reduction of the LDL receptor number. Sterol synthesis from sodium acetate is markedly inhibited, either in the presence or absence of LDL, whereas synthesis from mevalonic acid is unchanged. Cyclic AMP also induced a decrease in hydroxy methyl glutaryl coenzyme A reductase activity. These effects of cyclic AMP might be involved in some hormonal regulation of the LDL pathway and cholesterol metabolism in the liver.

Acetates↗