| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Primary dual defect of cholesterol and bile acid metabolism in liver of patients with intrahepatic calculi Shoda, J., B. F. He, et al. (1995), Gastroenterology 108(5): 1534-46. Abstract: BACKGROUND/AIMS: Intrahepatic calculi, which are characterized by cholesterol-rich pigment stones, are highly prevalent in East Asia. Their pathogenesis remains unknown. To elucidate the etiological factors underlying the formation of cholesterol-supersaturated bile, which leads to the formation of cholesterol-rich pigment stones cholesterol and bile acid de novo syntheses in the liver were studied. METHODS: Liver specimens were assayed for the catalytic activities and steady-state messenger RNA levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase. RESULTS: The activity of HMG-CoA reductase, consistent with the messenger RNA level, was significantly higher in 13 patients with intrahepatic grown pigment stones (11.2 +/- 1.3 pmol.min-1.mg protein-1 mean +/- SEM; P < 0.0001 for affected hepatic lobes and 13.4 +/- 1.7 P < 0.0001 for unaffected ones P < 0.0001) than in 19 control subjects (6.4 +/- 0.4) and in 29 patients with gallbladder cholesterol stones (2.1 +/- 0.1). On the other hand, the activity of 7 alpha-hydroxylase, consistent with the messenger RNA level, was significantly lower in patients with intrahepatic brown pigment stones (2.8 +/- 0.5 pmol.min-1.mg protein-1 P < 0.0001 for affected lobes and 2.6 +/- 0.5 P < 0.0001 for unaffected ones) than in control subjects (6.0 +/- 0.6) and in patients with cholesterol stones (5.1 +/- 0.5). CONCLUSIONS: In intrahepatic calculi, the formation of supersaturated bile and cholesterol-rich pigment stones may be attributed to the primary dual defect of up-regulated cholesterogenesis and down-regulated bile acid synthesis in the liver. |
| Primary hypertriglyceridemia with borderline high cholesterol and elevated apolipoprotein B concentrations. Comparison of gemfibrozil vs lovastatin therapy Vega, G. L. and S. M. Grundy (1990), Jama 264(21): 2759-63. Abstract: A common pattern of dyslipidemia is elevated levels of plasma triglyceride, borderline high total cholesterol, reduced high-density lipoprotein, and increased apolipoprotein B. This pattern of dyslipidemia frequently is associated with premature coronary heart disease. Nicotinic acid is the drug of first choice for this pattern. In this study, gemfibrozil and lovastatin were compared for their effects on the overall lipoprotein profile in 13 men with this type of dyslipidemia. Both drugs significantly reduced very-low-density lipoprotein and intermediate-density lipoprotein cholesterol levels, and both modestly raised high-density lipoprotein cholesterol levels. Gemfibrozil therapy, however, failed to reduce total cholesterol or total apolipoprotein B levels, whereas lovastatin therapy lowered levels of total cholesterol by 28%, low-density lipoprotein cholesterol by 33%, and total apolipoprotein B by 32%. Moreover, lovastatin therapy caused greater declines in lipoprotein cholesterol ratios than gemfibrozil therapy. Lovastatin thus seems to have certain advantages over gemfibrozil for treatment of elevated plasma triglyceride levels accompanied by borderline high total cholesterol and raised apolipoprotein B levels; therefore, lovastatin therapy should be considered as one approach for management of this condition. |
| Primary intrahepatic cholesterol stones. Report of one case and treatment with ursodeoxycholic acid Schillio, Y., G. Amouyal, et al. (1992), Dig Dis Sci 37(9): 1460-3. |
| Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study Downs, J. R., M. Clearfield, et al. (1998), Jama 279(20): 1615-22. Abstract: CONTEXT: Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. OBJECTIVE: To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinics in Texas. PARTICIPANTS: A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey NHANES III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 21 mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 17 mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 5 mg/dL) for men and 1.03 (0.14) mmol/L (40 5 mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 76 mg/dL) (63rd percentile). INTERVENTION: Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. MAIN OUTCOME MEASURES: First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. RESULTS: After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk RR, 0.63; 95% confidence interval CI, 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P =.003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. CONCLUSIONS: Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention. |
| Primary prevention of arteriosclerosis: cost-efficiency ratio in the determination of blood cholesterol Joven, J. and E. Vilella (1990), Med Clin (Barc) 94(9): 333-6. Abstract: Serum cholesterol, triglyceride, apoprotein Al and B, low-density and hig-density lipoprotein (LDL, HDL) cholesterol levels were quantitated, in two or more consecutive sample collections, in 289 middle aged males to assess the potential for misclassification of dyslipemia, according to the Sociedad Espanola de Arteriosclerosis and the USA National Cholesterol Education Program guidelines. They were grouped according to serum cholesterol values (less than 5.17 mmol/l, between 5.17 mmol/l and 6.17 mmol/l, and greater than 6.17 mmol/l) and misclassification was arbitrarily identified with different levels of the considered parameters. With cholesterol less than 5.17 mmol/l, misclassification was identified in 18.2% of the subjects, mainly with hypertriglyceridaemia or low HDL-cholesterol values. With cholesterol greater than 6.17 mmol/l there is a clear misclassification although obviated partially by the usual performance of complete routine lipoprotein analysis. Potential for misclassification is more evident when cholesterol was between 5.17 mmol/l and 6.17 mmol/l. To avoid such misclassification, HDL and LDL-cholesterol and serum cholesterol and triglyceride values should be measured in all subjects. Some data on the total cost in a general population screening are also presented; cost that on the author's opinion might be better invested under the control of a centralized institution. |
| Primary prevention of high blood cholesterol concentrations in the United States Goff, D. C., Jr., D. R. Labarthe, et al. (2002), Arch Intern Med 162(8): 913-9. Abstract: BACKGROUND: Mean concentrations of total cholesterol (TC) among adults have declined in the United States for decades. Whether the decline has been owing to prevention of high TC levels or treatment of high TC levels once present is not known. OBJECTIVE: To determine whether population-wide influences and/or the high-risk approach have been operating to produce the well-known decline in mean TC concentration in the US population. METHODS: We examined changes in the distribution of TC levels across US birth cohorts as sampled in the National Health Examination Survey and the National Health and Nutrition Examination Surveys I, II, and III. We tested the hypotheses that the age-adjusted 10th, 25th, 50th, 75th, and 90th percentiles of TC levels were lower in more recent US birth cohorts than in earlier cohorts. RESULTS: Data were analyzed for 49 536 participants born between 1887 and 1975 and examined at ages 18 through 74 years between 1959 and 1994. The 10th, 25th, 50th, 75th, and 90th percentiles of TC levels (adjusted for age, race, and sex) were estimated to be lower by 3.4, 3.9, 4.7, 5.7, and 7.1 mg/dL (0.09, 0.10, 0.12, 0.15, and 0.18 mmol/L), respectively, for every successive 10 years in date of birth (P<.001 for each estimate). CONCLUSIONS: The declines in TC levels associated with successive birth cohorts were greater at the upper aspect of the distribution, probably because of the combination of population influences and treatment effects. The differences seen at the lower percentiles support the contention that a strong prevention effect occurred in the US population from 1959 through 1994. Greater understanding of this dramatic shift in the distribution of TC levels could support future prevention efforts. |
| Primates highly responsive to dietary cholesterol up-regulate hepatic ACAT2, and less responsive primates do not Rudel, L. L., M. Davis, et al. (2002), J Biol Chem 277(35): 31401-6. Abstract: The role of liver acyl-CoA:cholesterol acyltransferase 2 (ACAT2), earlier shown to be the principal ACAT enzyme within primate hepatocytes, as a regulator of the hypercholesterolemia induced by dietary cholesterol was studied. At the end of low and high cholesterol diet periods, liver biopsies were taken from cynomolgus monkeys, a species highly responsive to dietary cholesterol, and less responsive African green monkeys. Liver cholesterol and cholesteryl ester concentrations were highest in cynomolgus monkeys fed cholesterol, despite the fact that in order to induce equivalent hypercholesterolemia, dietary cholesterol levels were 50% lower than was fed to green monkeys. Hepatic cholesteryl oleate secretion rate, measured during liver perfusion as an indicator of ACAT activity, was significantly higher in cynomolgus monkeys. Liver microsomal ACAT activity was 2-3-fold higher in cynomolgus monkeys than in green monkeys. The responses of ACAT2 were compared with those of ACAT1 that is found primarily in Kupffer cells. ACAT2 protein mass was significantly correlated to microsomal total ACAT activity in both species; ACAT1 mass was less well correlated. Dietary cholesterol induced a significant 3-fold increase of ACAT2 protein mass in cynomolgus monkeys, a much greater increase than was found for mRNA abundance; neither ACAT2 mRNA nor protein was diet-responsive in green monkeys. In cynomolgus monkeys but not in green monkeys, liver free cholesterol concentrations were elevated when cholesterol was fed and were correlated with ACAT2 protein levels. The data suggest a mechanism whereby the elevation of hepatic free cholesterol concentrations by dietary cholesterol, seen only in cynomolgus monkeys, resulted in higher ACAT2 protein levels in hepatocytes, either through increased production or stabilization of the protein. Regulation of ACAT2 gene transcription was not a factor. |
| Pro and con: low-density lipoprotein cholesterol lowering is and will be the key to the future of lipid management Pedersen, T. R. (2001), Am J Cardiol 87(5A): 8B-12B. Abstract: A wealth of data demonstrate that reduction of cholesterol levels is associated with benefit in reducing coronary artery disease risk. The magnitude of benefit observed with statin treatment, which acts primarily to reduce low-density lipoprotein cholesterol (LDL-C), is greater than that observed with any other lipid-modifying intervention, and data from large statin trials indicate that this benefit is caused by LDL-C reduction. Statin treatment is highly cost-effective compared with other accepted therapies, at least in the secondary prevention setting, and has a superior safety and tolerability profile. For the foreseeable future, LDL-C reduction will remain the goal of lipid-modifying therapy, and statins will remain the primary therapeutic modality for achieving that goal. |
| Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) is associated with higher levels of total cholesterol and LDL-cholesterol in male caucasian type 2 diabetes patients Zietz, B., N. Barth, et al. (2002), Exp Clin Endocrinol Diabetes 110(2): 60-6. Abstract: The peroxisome proliferator-activated receptor-gamma2 (PPAR(gamma2)) represents the transcriptional master regulator of adipocyte differentiation and therefore has been suggested as candidate gene for the pathogenesis of obesity, type 2 diabetes and related metabolic disorders. Aim of our study was to determine the frequency of a missense point mutation within exon 2 of PPAR(gamma2), Pro12Ala, and its possible association with metabolic parameters as well as diabetic retinopathy (in a population-based sample of 560 (318 male ad 242 female) type 2 diabetic patients. Subsequent to genomic PCR amplification, the Hpa-II RFLP analysis was used for genotyping. RESULTS: 436 (77.9%) subjects were homozygous for the wildtype allele (Pro/Pro), 118 (21.1%) were heterozygous (Pro/Ala) and 6 (1.1%) were homozygous for the mutated allele (Ala/Ala). Genotype frequency was calculated to be 0.81 for the wildtype and 0.19 for the mutated allele. These frequencies did not differ from non-diabetic cohorts examined earlier. In contrast to females, total cholesterol and LDL-cholesterol were significantly higher in males (Total cholesterol: 281.8 +/- 51.3 vs 253.1 +/- 49.8 mg/dl, p < 0.0001; LDL-cholesterol: 182.0 +/- 49.2 vs 155.6 +/- 42.0 mg/d, p < 0.0001) in the presence of the mutated allele as compared to the wildtype subgroup. No differences were found with respect to BMI, HbA1c, blood pressure and serum levels of leptin nor to prevalence of retinopathy. Pro12Ala polymorphism of PPAR(gamma2) gene is not associated with diabetic retinopathy but is associated with dyslipidemia in male type 2 diabetic patients. |
| Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits Yamakoshi, J., S. Kataoka, et al. (1999), Atherosclerosis 142(1): 139-49. Abstract: The aim of this study was to evaluate the antiatherosclerotic effect of proanthocyanidin-rich extracts from grape seeds in cholesterol-fed rabbits. Proanthocyanidin-rich extracts (0.1% and 1% in diets w/w) did not appreciably affect the changes in serum lipid profile of cholesterol-fed rabbits. The level of cholesteryl ester hydroperoxides (ChE-OOH) induced by 2,2'-azobis(2-amidinopropane-dihydrochloride (AAPH) were lower in the plasma of rabbits fed proanthocyanidin-rich extract plus cholesterol than in the plasma of rabbits fed cholesterol alone, but not in the low-density lipoprotein (LDL). Aortic malondialdehyde (MDA) content decreased in rabbits fed proanthocyanidin-rich extract. Feeding proanthocyanidin-rich extracts (0.1 and 1% in the diet) to rabbits significantly reduced severe atherosclerosis in the aorta. Immunohistochemical analysis revealed a decrease in the number of oxidized LDL-positive macrophage-derived foam cells in atherosclerotic lesions in the aorta of rabbits fed proanthocyanidin-rich extract. When proanthocyanidin-rich extract was administered orally to rats, proanthocyanidin was detected in the plasma by Porters method but not in the lipoproteins (LDL plus VLDL). In an in vitro experiment using human plasma, proanthocyanidin-rich extract added to the plasma inhibited the oxidation of cholesteryl linoleate in LDL, but not in the LDL isolated after the plasma and the extract were incubated in advance. These results suggested that proanthocyanidins, the major polyphenols in red wine, might trap reactive oxygen species in aqueous series such as plasma and interstitial fluid of the arterial wall, thereby inhibiting oxidation of LDL and showing an antiatherosclerotic activity. |
| Proapoptotic triterpene electrophiles (avicins) form channels in membranes: cholesterol dependence Li, X. X., B. Davis, et al. (2005), Biophys J 88(4): 2577-84. Abstract: Avicins, a family of triterpenoid saponins from Acacia victoriae, can regulate the innate stress response in human cells. Their ability to induce apoptosis in transformed cells makes them potential anticancer agents. We report that avicins can form channels in membranes. The conductance reached a steady state after each addition, indicating a dynamic equilibrium between avicin in solution and in the membrane. The high power dependence (up to 10) of the membrane conductance on the avicin concentration indicates the formation of multimeric channels, consistent with the estimated pore radius of 1.1 nm. This radius is too small to allow protein flux across the mitochondrial outer membrane, a process known to initiate apoptosis. Channel formation is lost when avicin's amphipathic side chain is removed, implicating this as the channel-forming region. A small difference in this side chain results in strong cholesterol dependence of channel formation in avicin G that is not found in avicin D. In neutral membranes, avicin channels are nonselective, but negatively-charged lipids confer cation selectivity (5:1, K(+):Cl(-)), indicating that phospholipids form part of the permeation pathway. Avicin channels in the mitochondrial outer membrane may favor apoptosis by altering the potential across this membrane and the intermembrane space pH. |
| Probing red cell membrane cholesterol movement with cyclodextrin Steck, T. L., J. Ye, et al. (2002), Biophys J 83(4): 2118-25. Abstract: We probed the kinetics with which cholesterol moves across the human red cell bilayer and exits the membrane using methyl-beta-cyclodextrin as an acceptor. The fractional rate of cholesterol transfer (% s(-1)) was unprecedented, the half-time at 37 degrees C being ~1 s. The kinetics observed under typical conditions were independent of donor concentration and directly proportional to acceptor concentration. The rate of exit of membrane cholesterol fell hyperbolically to zero with increasing dilution. The energy of activation for cholesterol transfer was the same at high and low dilution; namely, 27-28 Kcal/mol. This behavior is not consistent with an exit pathway involving desorption followed by aqueous diffusion to acceptors nor with a simple one-step collision mechanism. Rather, it is that predicted for an activation-collision mechanism in which the reversible partial projection of cholesterol molecules out of the bilayer precedes their collisional capture by cyclodextrin. Because the entire membrane pool was transferred in a single first-order process under all conditions, we infer that the transbilayer diffusion (flip-flop) of cholesterol must have proceeded faster than its exit, i.e., with a half-time of <1 s at 37 degrees C. |
| Probing the effects of membrane cholesterol in the Torpedo californica acetylcholine receptor and the novel lipid-exposed mutation alpha C418W in Xenopus oocytes Santiago, J., G. R. Guzman, et al. (2001), J Biol Chem 276(49): 46523-32. Abstract: The effects of cholesterol on the ion-channel function of the Torpedo acetylcholine receptor (nAChR) and the novel lipid-exposed gain in function alpha C418W mutation have been investigated in Xenopus laevis oocytes. We found conditions to increase the cholesterol/phospholipid (C/P) molar ratio on the plasma membrane of Xenopus oocytes from 0.5 to 0.87, without significant physical damage or change in morphology to the oocytes. In addition, we developed conditions to deplete endogenous cholesterol from oocytes using a methyl-beta-cyclodextrin incubation procedure without causing membrane instability of the cells. Methyl-beta-cyclodextrin was also used to examine the reversibility of the inhibitory effect of cholesterol on AChR function. Depletion of 43% of endogenous cholesterol from oocytes (C/P = 0.3) did not show any significant change in macroscopic response of the wild type, whereas in the alpha C418W mutant the same cholesterol depletion caused a dramatic gain-in-function response of this lipid-exposed mutation in addition to the increased response caused by the mutation itself. Increasing the C/P ratio to 0.87 caused an inhibition of the macroscopic response of the Torpedo wild type of about 52%, whereas the alpha C418W mutation showed an 81% inhibition compared with the responses of control oocytes. The wild type receptor did not recover from this inhibition when the excess cholesterol was depleted to near normal C/P ratios; however, the alpha C418W mutant displayed 63% of the original current, which indicates that the inhibition of this lipid-exposed mutant was significantly reversed. The ability of the alpha C418W mutation to recover from the inhibition caused by cholesterol enrichment suggests that the interaction of cholesterol with this lipid-exposed mutation is significantly different from that of the wild type. The present data demonstrate that a single lipid-exposed position in the AChR could alter the modulatory effect of cholesterol on AChR function. |
| Problems with the National Cholesterol Education Program recommendations for cholesterol analytical performance Krouwer, J. S. (2003), Arch Pathol Lab Med 127(10): 1249. |
| Problems with the report of the Expert Panel on blood cholesterol levels in children and adolescents Newman, T. B., A. M. Garber, et al. (1995), Arch Pediatr Adolesc Med 149(3): 241-7. Abstract: An Expert Panel convened by the National Cholesterol Education Program has recommended selective screening and treatment of children for high blood cholesterol levels, based on family history of cardiovascular disease or high blood cholesterol. This recommendation is problematic for several reasons. First, the recommended diets are likely to cause only a slight decrease in low-density lipoprotein cholesterol levels, the projected benefits of which will be offset by a similar decrease in high-density lipoprotein cholesterol levels. Lack of efficacy of the recommended diets could lead to use of more restrictive diets or to cholesterol lowering drugs. Second, even under optimistic assumptions, beneficial effects of cholesterol intervention will be small and delayed for many decades. As a result, childhood cholesterol-lowering efforts will not be cost-effective. Third, the Expert Panel's recommendations do not address important gender differences. Girls have higher average cholesterol levels than boys. They will therefore qualify for more dietary and drug treatment despite their lower age-adjusted risk of heart disease and the lack of association between cholesterol levels and cardiovascular mortality in women. Finally, recent evidence from randomized trials, cohort studies, and animal experiments suggests that cholesterol lowering may have serious adverse effects. This evidence was not discussed in the Expert Panel's report. Given current evidence, any screening and treatment of children for high blood cholesterol levels is, at best, premature. |
| Probucol improves endothelial-dependent relaxation and decreases vascular superoxide production in cholesterol-fed rabbits Inoue, N., Y. Ohara, et al. (1998), Am J Med Sci 315(4): 242-7. Abstract: Recent data indicate that hypercholesterolemia increases endothelial superoxide anion (O2-) production, and that this diminishes the bioactivity of nitric oxide produced in the endothelium. Probucol, a drug commonly employed for treatment of hypercholesterolemia, has antioxidant properties and inhibits oxidation of low density lipoproteins in vitro. We tested the hypothesis that probucol would decrease vascular.O2- production and improve endothelium-dependent relaxations in cholesterol-fed rabbits. Rabbits were divided into four groups: 1) a control group fed a standard diet; 2) a probucol group fed a standard diet containing 0.3% probucol; 3) a hypercholesterolemic group fed a diet containing 0.5% cholesterol; 4) a hypercholesterolemia-probucol group fed a diet containing 0.5% cholesterol and 0.3% probucol. The cholesterol-rich diet markedly increased plasma total cholesterol level and lipid peroxidation in the plasma, as reflected by thiobarbituric acid-reactive substances (TBARS). This concentration of probucol did not lower plasma cholesterol, but markedly reduced TBARS in the plasma of cholesterol-fed rabbits. Aortic segments from cholesterol-fed rabbits produced 1.8-fold more.O2- (assessed by lucigenin-enhanced chemiluminescence) and decreased endothelium-dependent vascular relaxations to acetylcholine compared to vessels from normal rabbits. In cholesterol-fed rabbits, probucol treatment normalized both.O2- production and endothelium-dependent relaxations to acetylcholine. In control rabbits, probucol had no effect on either of these parameters. We conclude that probucol treatment may prevent.O2(-)-induced inactivation of endothelium-derived nitric oxide and reduce vascular oxidant stress via reducing the level of.O2-. |
| Probucol increases the selective uptake of HDL cholesterol esters by Hep G2 human hepatoma cells Pfeuffer, M. A., B. M. Richard, et al. (1992), Arterioscler Thromb 12(7): 870-8. Abstract: A previous study in rats showed that even though probucol substantially lowers high density lipoprotein (HDL) levels, near-normal mass transport of HDL cholesterol esters (CE) to the liver is maintained by the induction of "selective" (direct) uptake of HDL CE. The present study describes a parallel result in cultured Hep G2 human hepatoma cells. Cells were preincubated in the presence or absence of probucol before measuring the uptake of doubly labeled HDL3 in the absence of probucol. Preincubation with probucol decreased the uptake of HDL3 particles (iodine-125-labeled N-methyltyramine cellobiose-apolipoprotein 125I-NMTC-apo A-I uptake) but increased the uptake of 3Hcholesteryl oleyl ether in excess of 125I-NMTC-apo A-I (i.e., selective uptake) in a dose-dependent fashion. The reversibly cell-associated pool of CE tracer, a precursor for selective uptake, enlarged on probucol treatment, but the increase was not in proportion to the increase in selective uptake. HDL3 particle uptake decreased on probucol treatment. The decrease was evident after less than 20 minutes of probucol exposure and was maximal after 6 hours; in contrast, HDL3 CE selective uptake increased only after greater than 13 hours and had not reached a plateau after 20 hours. Thus, effects on particle uptake and selective uptake were dissociated in time. |
| Probucol inhibits mononuclear cell adhesion to vascular endothelium in the cholesterol-fed rabbit Ferns, G. A., L. Forster, et al. (1993), Atherosclerosis 100(2): 171-81. Abstract: Mononuclear cells, isolated from the blood of hyperlipidaemic patients, are hyper-reactive and possess an increased propensity to adhere to vascular endothelial cells. Hyperlipidaemia is also associated with a dysfunctional endothelium, to which mononuclear cells stick with greater avidity. In order to assess the importance of lipid peroxidation and free-radical generation in these processes, we have investigated the effects of probucol on mononuclear cell adhesion to vascular endothelial cells in vivo and in vitro in the cholesterol-fed rabbit. New Zealand White rabbits were fed either: (i) control chow (n = 15), (ii) 2% cholesterol (n = 11), or (iii) 2% cholesterol with 1% probucol (n = 11). Mononuclear cell adherence to endothelium in the common carotid artery was assessed 5 weeks after the start of the experimental diet using the Hoechst 33342 staining technique. The 2% cholesterol diet caused a more than 6-fold increase in mean mononuclear cell adherence (P < 0.001). Concurrent probucol therapy abrogated the effects of cholesterol feeding, and in animals in this group, in vivo mononuclear cell adherence did not differ significantly from control animals. In vivo mononuclear cell adherence was directly related to serum cholesterol levels (r = 0.68, P < 0.0001) and inversely related to serum probucol concentrations (r = -0.63, P < 0.002). Concurrent probucol therapy also reduced the in vitro binding of mononuclear cells, isolated from hypercholesterolaemic animals, to endothelial cell monolayers (P < 0.01). These data suggest that the increased binding of mononuclear cells to vascular endothelium of cholesterol-fed rabbits may be a free radical mediated process that is inhibited by antioxidants. |
| Probucol inhibits neointimal thickening and macrophage accumulation after balloon injury in the cholesterol-fed rabbit Ferns, G. A., L. Forster, et al. (1992), Proc Natl Acad Sci U S A 89(23): 11312-6. Abstract: Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis. |
| Probucol promotes reverse cholesterol transport in heterozygous familial hypercholesterolemia. Effects on apolipoprotein AI-containing lipoprotein particles Adlouni, A., M. El Messal, et al. (2000), Atherosclerosis 152(2): 433-40. Abstract: In order to investigate the effect of Probucol therapy on reverse cholesterol transport, apo AI-containing lipoprotein particles were isolated and characterized, and their cholesterol effluxing capacity and LCAT activity were assayed in four familial hypercholesterolemia patients before and after 12 weeks of Probucol therapy. Four major subpopulations of apo A-containing lipoprotein particles are separated before and after drug treatment; LpAI, LpAI:AII, LpAIV, LpAI:AIV:AII. Probucol reduces both total plasma and LDL-cholesterol (-17 and -14%, respectively). Apo B decreases slightly (-7.6%). Plasma HDL-cholesterol and apo AI decrease by 36.6 and 34.7%. LpA-I showed a marked decrease (-46%). Moreover, plasma LCAT and CETP activities were markedly increased under Probucol treatment. Analysis of lipoprotein particles showed that Probucol induces a decrease of protein content and an increase of cholesterol and triglycerides contents. Interestingly, Probucol induces an enhancement of LCAT activity in LpAI (4.5-fold). This drug induces a trend toward greater cholesterol efflux from cholesterol-preloaded adipose cells promoted by Lp AI and Lp AIV but not by Lp AI:AII. This study confirms the hypothesis, in addition to the lowering LDL-cholesterol levels and antioxidant effects of Probucol, that HDL reduction was not an atherogenic change in HDL system but may cause an antiatherogenic action by accelerating cholesterol transport through HDL system, promoting reverse cholesterol transport from peripheral tissues. |