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PubMed1989

Role of biologically modified low-density lipoprotein in atherosclerosis.

It has been proposed that low-density lipoprotein (LDL) may become very atherogenic if it undergoes a cell-mediated oxidative modification within the arterial wall. Recently, several lines of evidence have been reported that indicate that such oxidative reactions occur in vivo and that oxidized LDL accumulates in lesions. In addition, it has been shown that treatment of spontaneously atherosclerotic Watanabe heritable hyperlipidemic rabbits with probucol, a very potent antioxidant, inhibits formation or progression of early lesions, suggesting a pathogenic role for oxidized LDL in atherogenesis.

Animals↗
PubMed1990

Hydroxymethylglutaryl coenzyme A reductase inhibitors as monotherapy in the treatment of hypercholesterolemia.

A variety of double-blind studies have compared the efficacy of hydroxymethylglutaryl coenzyme A reductase inhibitors (lovastatin and simvastatin) with that of control agents (cholestyramine, fibrates and probucol) in patients with type IIA or IIB primary hypercholesterolemia. Results have shown that both lovastatin and simvastatin are more effective than the standard therapies with regard to reducing total and low-density lipoprotein cholesterol. Decreases in triglycerides and increases in high-density lipoprotein cholesterol were generally greater with fibrates. Ongoing studies are assessing the benefits of lovastatin and simvastatin in reducing the incidence of mortality from coronary artery disease, as well as causing regression of coronary atheroma.

Bezafibrate↗
PubMed1992

Cholesterol-lowering drugs as cardioprotective agents.

A detailed overview of the various forms of hyperlipidemia/dyslipidemia that constitute a major risk factor for coronary heart disease and a detailed discussion of the various types of cholesterol-lowering drugs are presented. The importance of identifying the type of dyslipidemia with respect to the choice of treatment is emphasized, as is the use of nonpharmacologic intervention, i.e., diet, exercise, and weight loss. The appropriate use and benefits of bile acid sequestrants, nicotinic acid, fibric acids, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and probucol are individually discussed, whereas nonpharmacologic approaches used in conjunction with the drugs are recommended emphatically.

Anticholesteremic Agents↗
PubMed1994

Mechanistic studies of sterol carrier protein-2 effects on L-cell fibroblast plasma membrane sterol domains.

The factors which regulate intermembrane sterol domains and exchange in biomembranes are not well understood. A new fluorescent sterol exchange assay allowed correlation of changes in polarization to sterol transfer. Analysis of spontaneous sterol exchange between L-cell plasma membranes indicated two exchangeable and one very slowly or nonexchangeable sterol domain. The exchangeable domains exhibited half-times of 23 and 140 min with fractional contributions of 5 and 30%, respectively. Sterol carrier protein-2 (SCP-2) enhanced sterol exchange between L-cell plasma membranes and altered sterol domain size in a concentration dependent manner. Previous model membrane studies indicate that SCP-2 alters sterol domains and exchange through interaction with anionic phospholipids. In contrast to these observations, the ionic shielding agents KCl, low pH, or neomycin were either totally or partially ineffective inhibitors of SCP-2 action in L-cell plasma membrane exchanges. Thus the mechanism of SCP-2 in sterol transfer appears to be less charge dependent in L-cell plasma membranes than in model membranes. The cholesterol lowering drug probucol was also capable of altering the sterol exchange kinetics.

Amino Acid Sequence↗
PubMed1983

Subpopulations of apolipoprotein A-I in human high-density lipoproteins. Their metabolic properties and response to drug therapy.

In this study immunological procedures were used to detect and quantify high-density lipoprotein (HDL) particles of differing apolipoprotein A composition. In the plasma of eight healthy female subjects, 45% of the total apolipoprotein A-I existed in particles (called '(AI)HDL') devoid of apolipoprotein A-II. The remainder circulated in association with apolipoprotein A-II at a molar ratio of approximately 1:1. Nicotinic acid selectively raised the plasma apolipoprotein A-I/A-II ratio by increasing the proportion of (AI)HDL particles. Probucol produced the opposite effect, lowering the plasma concentration of these particles. The kinetic properties of apolipoprotein A-I in total HDL and in the (AI)HDL particle were the same despite the fact that apolipoprotein A-I equilibration between these two species was incomplete. Therefore, there appear to be at least two apolipoprotein A-containing particle populations in HDL which are immunochemically and metabolically distinct.

Adolescent↗
PubMed1989

Modification of cellular fatty acid composition of Hep-G2 cells: effect of antioxidants on cholesterol esterification and secretion.

Modification of fatty acid composition of Hep-G2 cells was achieved by 7-9 days of supplementation of culture medium with palmitic, oleic or linoleic acid. Cholesterol release into serum-free culture medium during 24 h of incubation was significantly lower in cells supplemented with linoleic acid, when compared to those supplemented with palmitic, oleic or no additional fatty acid. In cells cultured in the presence of linoleic acid, less [3H]cholesterol was esterified to cholesteryl ester and the mass of cholesteryl ester was significantly lower than in cells cultured with palmitic acid or with no additional fatty acid. The reduction in [3H]cholesterol secretion and the impairment in cholesterol esterification in linoleic acid-treated cells was prevented by addition of butylated hydroxytoluene or probucol concurrently with the fatty acid. The antioxidants also increased esterification and [3H]cholesterol release in cells supplemented with the other fatty acids. It is suggested that cholesterol secretion and esterification are sensitive to peroxidation.

Antioxidants↗
PubMed1991

Oxidative modification of glycated low density lipoprotein in the presence of iron.

This is the first observation for contributing to the glycation of low density lipoprotein (LDL) to oxidative modification of its own lipids and protein. Human plasma LDL was glycated by incubation with glucose (G-LDL). Glucose incorporated into apoprotein B was approximately 10 mol/mol of apoprotein (2.8% modification of lysine residues) and 84% of G-LDL was adsorbed on phenylboronate affinity column. G-LDL incubated with Fe3+ for 4 h caused a significantly higher level of lipid peroxidation than U-LDL (untreated with glucose), and a higher molecular weight protein was observed in apoprotein B on SDS-polyacrylamide gel electrophoresis (SDS-PAGE), increasing with incubation period. Corresponding to change on SDS-PAGE, G-LDL exposed to Fe3+ moved faster than G-LDL per se or U-LDL to anode on agarose gel electrophoresis. The higher the Fe3+ concentration, the more lipid peroxidation was caused. Alpha-tocopherol or probucol suppressed the lipid peroxidation of G-LDL exposed to Fe3+.

Electrophoresis, Polyacrylamide Gel↗
PubMed1992

Chemotaxis of human blood monocytes toward endothelin-1 and the influence of calcium channel blockers.

The adherence of monocytes to the arterial endothelium followed by its migration into the arterial intima is the earliest event in atherogenesis. The vasoconstrictive peptide, Endothelin-1 (ET-1), is elevated in patients with atherosclerosis. We were interested to know whether ET-1 was a chemoattractant for blood monocytes. Using the modified membrane filter technique for chemotaxsis assessment, ET-1 increased monocyte chemotaxis in a dose-dependent manner. Ca2+ channel blockers, Nifedipine, Diltiazem and Verapamil (5 microM), reduced ET-1 chemotaxsis more than 60% (P < 0.001). Aspirin and Indomethacin (1 mM and 100 microM, respectively) reduced migration by 23% (P < 0.05). Alpha-Lipoic acid, Probucol and Neomycin (100 microM) were also migration inhibitory (37%, P < 0.01). These results suggest that ET-1 is a strong chemoattractant for blood monocytes; Ca2+ influx is probably the major stimulus for the accelerated migration induced by ET-1.

Aspirin↗
PubMed1996

Structure-function relationships of calcium antagonists. Effect on oxidative modification of low density lipoprotein.

Human low density lipoprotein (LDL) incubated with active Ca2+ antagonists from three different chemical groups, 1,4-dihydropyridines that are of reduced activity as Ca2+ antagonists, vitamin E, and probucol, was more resistant than control to copper- or human monocyte-induced oxidation, as assessed by thiobarbituric acid reactive substance (TBARS) content, degradation by J774 macrophages, and relative electrophoretic mobility on agarose gel. In the copper-induced oxidation system, the drugs tested reduced the TBARS levels of LDL in a concentration-dependent manner. The order of potency was vitamin E > felodipine > 2-chloro analog of nifedipine > nifedipine > amlodipine, nitrendipine, verapamil > diltiazem. In agreement with the results of the TBARS assay, felodipine (25 microM) was also the most effective calcium antagonist in the degradation assay, inducing a significant (P<0.05) 97 +/- 2% reduction in the amount of oxidized [125I]LDL degraded by J774 macrophages compared with nifedipine and its 4-nitro analog, amlodipine, and verapamil. The relative mobility of oxidized LDL on agarose gel was reduced significantly (P<0.05) by felodipine (50 microM) and amlodipine (25 and 50 microM) when compared with control, and was similar to that of native LDL, suggesting an effect of these drugs on the net negative charge of oxidized LDL. In the cell-induced oxidation system, both nifedipine and felodipine (25 microM) induced significant (P<0.05) reductions in the TBARS content of LDL (96 +/- 2 and 65 +/- 9%, respectively) compared with amlodipine, verapamil and the 4-nitro analog of nifedipine. However, in this oxidation system nifedipine was a more effective antioxidant than felodipine. Analysis of the structure-function relationships for the effect of 1,4-dihydropyridines on the oxidative modification of LDL suggests an important role for the 2-substitution of the phenyl ring, and an essential role for the dihydropyridine ring. This study clearly shows that Ca2+ antagonists from different chemical groups have a concentration-dependent effect as antioxidants against LDL oxidation. However, the order of potency of the drug depends on the oxidation system and the assay used to measure the antioxidant effect. Our data suggest that such a protective effect of Ca2+ antagonists against LDL oxidation could play a role in the antiatherosclerotic effect of these drugs.

Animals↗
PubMed1996

The mitogenic effect of H2O2 for vascular smooth muscle cells is mediated by an increase of the affinity of basic fibroblast growth factor for its receptor.

Increased generation of active oxygen species such as hydrogen peroxide (H202) may be important in vascular smooth muscle cell growth associated with atherosclerosis and restenosis. In this work, we showed that H202 was a potent mitogen for growth-arrested cultured human aortic smooth muscle cells (SMC), stimulating an increase in cell number at 10 nM to 100 microM concentration. This effect was inhibited in a dose-dependent manner by catalase, deferoxamine, dimethylthiourea or probucol showing that it was dependent on the oxidative activity of H202. H202-induced SMC proliferation was strongly and specifically inhibited by a neutralizing monoclonal antibody directed against basic fibroblast growth factor (bFGF) but was not due to increased expression of bFGF or the bFGF receptor-1 (FGFR-1) by SMC. H202 strongly increased the affinity of bFGF for its receptor-1 at the surface of the SMC, therefore showing that the mitogenic effect of H202 might occur through a direct effect on the bFGF receptor.

Antioxidants↗
PubMed1985

Plasma carnitine and lipid-lowering drugs.

Oral carnitine has been reported to have a lipid-lowering effect with concomitant elevation of high density lipoprotein cholesterol (HDL-C) levels in normo- and hyperlipidemic individuals. Unexpectedly, basal carnitine concentrations were found to be abnormally high in subjects receiving a combination of probucol (1 g/day) and clofibrate (2 g/day), and who also had reduced HDL-C levels. Changes in plasma carnitine levels were found to correlate with clofibrate therapy and to be readily reversible with cessation of this drug. These increases of circulating carnitine were not accompanied by a rise in HDL-C.

Carnitine↗
PubMed1990

Reduction of serum lipoprotein(a) levels in hyperlipidaemic patients with alpha-tocopheryl nicotinate.

The effect of low dose (600 mg/day) alpha-tocopheryl nicotinate on serum lipoprotein(a) (Lp(a] concentration was studied in 28 hyperlipidaemic patients. Serum lipids, lipoproteins and apolipoproteins, except for Lp(a), tended to increase after treatment. In particular, the changes in HDL-cholesterol and apo C-II levels were statistically significant. On the other hand, serum Lp(a) levels in all patients decreased significantly after 2 months of treatment. Furthermore, no difference between before and after treatment was observed in the group with initial Lp(a) levels less than 18 mg/dl, whereas Lp(a) concentrations decreased significantly after treatment in the group with levels greater than or equal to 18 mg/dl. The effects of probucol and alpha-tocopheryl nicotinate on serum Lp(a), total cholesterol and HDL-cholesterol were entirely different. Possible mechanisms of alpha-tocopheryl nicotinate on serum Lp(a) and lipoprotein metabolism are discussed.

Adult↗
PubMed1990

Aortic endothelial cell damage induced by beta-VLDL and macrophages in vitro.

We performed an in vitro study to assess damage to swine aortic endothelial cells by rabbit beta-VLDL and/or rabbit peritoneal macrophages. Incubation of cultured aortic endothelial cells with beta-VLDL, macrophages, or macrophage lysate induced endothelial cell damage time- and dose-dependently as estimated by [3H]adenine release. Incubation of endothelial cells with both beta-VLDL and macrophages produced a synergistic effect on the increase of [3H]adenine release. Pretreatment of the endothelial cells with some kinds of antioxidants (probucol 50 micrograms/ml, vitamin E 50 microM, superoxide dismutase-polyethylene glycol 0.5 mg/ml, or catalase-polyethylene glycol 0.5-1.0 mg/ml) significantly prevented the endothelial damage by beta-VLDL or macrophage lysate. We conclude that beta-VLDL and/or macrophages could induce endothelial cell damage and that some kinds of antioxidants could prevent it.

Adenine↗
PubMed1990

Oxidation of cholesteryl linoleate by human monocyte-macrophages in vitro.

The amount of cholest-5-en-3 beta,7 beta-diol (CD) was significantly higher in cultures of human monocytes incubated with cholesteryl linoleate-bovine serum albumin (CL/BSA) artificial lipoproteins than in no-cell control incubations of CL/BSA. CD production by monocytes was almost completely inhibited by the radical scavengers butylated hydroxytoluene (BHT), probucol, and alpha-tocopherol, and was partially inhibited by the metal chelator EDTA. The production of CD was accompanied by decrease in linoleic acid. CD amounts were negligible in incubations of monocytes with cholesteryl oleate/BSA (CO/BSA) or cholesterol/BSA (C/BSA). Ability to produce CD from CL/BSA appeared to increase with age in culture of human monocyte-macrophages. Considerable variations were observed in the CD production from CL/BSA by monocytes from different blood donations. Higher levels of CD production appeared more common with monocytes from men than from women. The significance of these results in the context of human atherosclerosis is discussed.

Arteriosclerosis↗
PubMed1993

Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally believed that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase because they cannot respond to an increased demand for hepatic cholesterol by up-regulation of LDL-receptor activity. In this paper we show that serum cholesterol in a homozygous FH patient with a receptor-negative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combination with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previously undescribed point mutation in exon 11 introduces a premature termination codon at residue 540 in the protein; the mutant protein is predicted to be truncated in the domain with homology to the epidermal growth factor precursor. Cultured cells from the patient were unable to bind, internalise or degrade LDL by the receptor pathway and there was no immunodetectable LDL receptor protein in the cells. Thus the lipid lowering effect of simvastatin in this individual must involve mechanisms other than stimulation of LDL receptors.

Adolescent↗
PubMed1994

Effect of the acyl-CoA:cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits.

E5324, n-butyl-N'-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6- methylphenyl]urea, a novel and orally absorbable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated for its antiatherosclerotic and antihyperlipidemic effects in cholesterol-fed hypercholesterolemic rabbits. When administered concurrently with a high-cholesterol (0.5% cholesterol) diet for 12 weeks, E5324 (0.0025%, 0.005% and 0.01% in diet) lowered plasma total cholesterol levels dose-dependently (by about 55%-87% at the end of the experiment compared with the control) and also reduced atherosclerotic plaque formation (about 90% reduction at the highest dose; P < 0.01). In pre-established hypercholesterolemic rabbits, which had been pre-fed a high-cholesterol diet for 8 weeks, E5324 administered in the same diet at a dose of 0.005%, 0.01% or 0.02% for 4 weeks significantly reduced plasma cholesterol levels dose-dependently. Cholesterol content and ACAT activity in the aortic arch were also decreased (by about 72% and 58% at the highest dose, respectively) compared with the control. Another ACAT inhibitor, CI-976, had a similar action, but cholestyramine and probucol (2% and 1% in diet, respectively) lacked anti-atherosclerotic activity in this model. Furthermore, when pre-established hypercholesterolemic rabbits were fed normal rabbit chow diet with or without 0.02% E5324 for 4 weeks, changes in plasma cholesterol levels were similar in both E5324-treated and control groups. On the other hand, E5324 significantly reduced cholesterol content and ACAT activity in the aortic arch (by about 52% and 50%, respectively) compared with the control group. These results indicate that E5324 not only has hypocholesterolemic activity, but also may have a direct effect on the arterial wall in experimental atherosclerosis.

Anilides↗
PubMed1995

Toxicity of oxidized low density lipoproteins for vascular smooth muscle cells and partial protection by antioxidants.

Oxidized low density lipoprotein (oxLDL) is known to be toxic to a variety of cell types, but relatively little is known about the toxic effects of oxLDL on vascular smooth muscle cells (SMC). We found that LDL oxidized by incubation with 5 microM cupric ions was toxic to cultured porcine SMC when administered at concentrations of 25 micrograms protein/ml and higher. The toxicity was demonstrated whether cells were proliferating or not, and was more evident in the presence of 0.4% lipoprotein-deficient serum than in 10%. Because of recent evidence that 7-ketocholesterol and 7-hydroxycholesterol are toxic species in copper-oxidized LDL, inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase was hypothesized as a mechanism of toxicity. However, mevalonic acid, the product of this enzyme, failed to protect against the toxicity of either oxLDL or the pure oxysterols. Alpha-tocopherol, alpha-tocopherol acetate, probucol, butylated hydroxytoluene, and deferoxamine provided partial protection to SMC exposed to oxLDL. These results suggested a toxic role for newly initiated lipid peroxidation, either in cells or in media oxLDL. Cellular lipid peroxidation appeared more likely, since no further oxidation of media oxLDL was demonstrated in the presence or absence of antioxidants. Overall, the results suggest that toxicity of copper-oxidized LDL for SMC is multifactorial and differs from the previously described toxicity of iron-oxidized LDL for fibroblasts.

Animals↗
PubMed1991

Inhibition of proliferation of fibroblasts by lazaroids (21-aminosteroids).

Lazaroids (21-aminosteroids) are a novel group of compounds that inhibit lipid peroxidation in biological systems and protect cells from oxidative damage during tissue injury. In vivo efficacy of lazaroids has been demonstrated in a variety of animal models of traumatic or ischemic injury of central nervous system (1-6). However, very little is known about the affects of lazaroids on cellular responses associated with tissue repair and remodeling eg cell proliferation and synthesis of extracellular matrix. In the present study, we show that lazaroids and certain related compounds inhibit cell proliferation in vitro. Light microscopic examination and determination of release of intracellular enzyme, lactate dehydrogenase suggested that cell growth inhibition by lazaroids was not due to cell death resulting from cytotoxic effects. Examination of several lazaroid related antioxidants and other known antioxidants eg vitamin E and Probucol showed that compounds with similar antioxidant potential did not exhibit identical antiproliferative activity, suggesting that cell growth inhibition by lazaroids may be unrelated to their antioxidant action. These results may have implication in the therapeutic actions of lazaroids.

Animals↗