Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that alpha-tocopherol, a safe and effective antioxidant, be used in clinical trials to evaluate the ability of antioxidant therapy to inhibit atherosclerosis. Recent reports, however, have raised the possibility that there may be greater enrichment of plasma low density lipoprotein (LDL) in alpha-tocopherol resulting from the use of the naturally occurring RRR-alpha-tocopherol isomer compared with the other isomers present in the synthetic racemic form of alpha-tocopherol. Therefore, we fed equal dosages (1,600 mg/day) of the two forms of vitamin E to 16 men and women for 8 weeks and compared the effects of this supplementation on the susceptibility of isolated lipoproteins to oxidation. Neither form of vitamin E had appreciable effects on lipid or lipoprotein levels. alpha-Tocopherol levels in LDL increased at a similar rate in both groups and were nearly twofold higher than baseline levels by the end of the study. The susceptibility of LDL to oxidation was measured by formation of conjugated dienes, lipid peroxides, and thiobarbituric acid-reactive substances, as well as by macrophage degradation of LDL exposed to oxidizing conditions in vitro. The susceptibility of LDL to oxidation was decreased in both vitamin E groups compared with the baseline value, and this reduction occurred to a similar extent in both vitamin E-supplemented groups. alpha-Tocopherol levels in LDL also strongly correlated with all measures of LDL oxidation. This study demonstrates that, at this dosage, supplementation with either the natural or synthetic form of alpha-tocopherol provided equal antioxidant protection to LDL.
 ...
PMID:Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans. Effects on lipid levels and lipoprotein susceptibility to oxidation. 846 95

Patients with diabetes mellitus have an increased risk of premature atherosclerosis, which may be due in part to increased oxidizability of low-density lipoprotein (LDL). Numerous studies have shown that alpha-tocopherol can reduce the oxidative susceptibility of LDL in normoglycemic subjects; however, there are few studies in persons with diabetes. In addition, alpha-tocopherol may reduce the extent of protein glycation. Therefore, the objective of the present study was to assess the effect of RRR-alpha-tocopheryl acetate supplementation on LDL oxidizability and protein glycation in persons with diabetes without evidence of vascular disease. Twenty-eight persons with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) were randomly assigned to receive either placebo or 1632 mg (1200 IU) RRR-alpha-tocopherol/d, as tocopheryl acetate, for 8 wk. Plasma and LDL antioxidant concentrations and LDL oxidizability were assessed at both 0 and 8 wk. Plasma and LDL concentrations of alpha-tocopherol were significantly increased in the supplemented group only. Compared with the placebo group, the alpha-tocopherol-supplemented group had significant reductions in LDL oxidizability at 8 wk, as shown by the time-course curves of conjugated diene and lipid peroxide formation. Also, alpha-tocopherol supplementation produced a significant prolongation in the lag phases of both assays, which was evident in both the NIDDM and IDDM subgroups. However, there were no significant changes in glycated hemoglobin or in glycated plasma proteins after alpha-tocopherol supplementation. Thus, alpha-tocopherol supplementation may be beneficial in reducing LDL oxidizability in patients with diabetes.
 ...
PMID:RRR-alpha-tocopheryl acetate supplementation at pharmacologic doses decreases low-density-lipoprotein oxidative susceptibility but not protein glycation in patients with diabetes mellitus. 861 60

Consumption of a range of dietary antioxidants may be beneficial in protecting low density lipoprotein (LDL) against oxidative modification, as studies have demonstrated that antioxidants other than vitamin E may also function against oxidation of LDL in vitro. In the present study, the effect of polyphenol antioxidants on the susceptibility of LDL to copper-mediated oxidation was investigated after feeding semi-purified diets to 3 groups of New Zealand white (NZW) rabbits. All diets comprised 40% energy as fat with 17% energy as oleic acid. Dietary fatty acid compositions were identical. Oils with different polyphenol contents were used to provide the dietary source of oleic acid-refined olive oil, extra virgin olive oil and Trisun high oleic sunflower seed oil. Polyphenolic compounds (hydroxytyrosol and p-tyrosol) could only be detected in the extra virgin olive oil. Vitamin E was equalised in all diets. LDL oxidizability in vitro was determined by continuously monitoring the copper-induced formation of conjugated dienes after 6 weeks of experimental diet feeding. The lag phase before demonstrable oxidation occurred was significantly increased in the high polyphenol, extra virgin olive oil group (P < 0.05) when compared with combined results from the low polyphenol group (refined olive oil and Trisun), even though the LDL vitamin E concentration in the high polyphenol group was significantly lower. The rate of conjugated diene formation was not influenced by the presence of dietary polyphenols. Results demonstrate that antioxidants, possibly phenolic compounds which are present only in extra virgin olive oil, may contribute to the endogenous antioxidant capacity of LDL, resulting in an increased resistance to oxidation as determined in vitro.
Atherosclerosis 1996 Feb
PMID:Dietary non-tocopherol antioxidants present in extra virgin olive oil increase the resistance of low density lipoproteins to oxidation in rabbits. 864 56

Oxidation of low-density lipoprotein (LDL) probably plays an important part in atherosclerosis. Vitamin E (alpha-tocopherol) is a potent antioxidant carried in LDL. It increases the resistance of LDL to oxidation, thereby, among other things, inhibiting foam cell formation and proliferation of smooth muscle cells. Some animal experiments have indicated that vitamin E retards the development of atherosclerotic lesions. Observational studies (case-control and cohort) have shown that long-term treatment with vitamin E is associated with lower incidence of coronary heart disease in men and women alike. Randomisation to vitamin E in a large placebo controlled trial gave a nonsignificant reduction in mortality from ischemic heart disease. Although vitamin E seems to reduce the risk of coronary heart disease, randomised trials of adequate size are necessary in both secondary and primary prevention in order to test this. Such trials are in progress.
 ...
PMID:[Can vitamin E prevent development of coronary heart disease?]. 865 Jun 39

Homozygous familial hypercholesterolemia (HFH) results from a mutation affecting both the structure and function of a cell surface receptor that removes low density lipoproteins (LDL) from plasma. The disorder is characterized by autosomal dominant inheritance, a lifelong elevation in the concentration of LDL-bound cholesterol in blood and by cholesterol deposits that form xanthomas and early coronary artery disease. HFH patients, as a result of the increased levels and prolonged residence time of LDL in plasma, have a strong tendency toward accumulation of LDL-cholesterol in the arterial wall causing premature atherosclerosis. Selective LDL-apheresis (LA) on dextran/sulphate cellulose columns is the best therapy reducing mortality of these patients. We previously showed that prolonged lifelong enhanced LDL oxidation in HFH. LDL undergo oxidation before being taken up by macrophages then transformed into foam cells. At the present time, the relevance of the in vitro macrophages studies to the accumulation of cholesterol esters in scavenger cells of HFH patients is not yet established. The aim of this study was to investigate LDL oxidation, induced by xanthine (2 mM)+xanthine oxidase (100 mU), and cholesterol esterification in macrophages, in 8 HFH patients before and after LA. LDL peroxidation by conjugated-diene absorbance showed an increased resistance against oxidation after LA: lag time 129 +/- 25 vs 112 +/- 27 min, p < 0.05; diene production 9.1 +/- 2.1 vs 13.9 +/- 2.5 nM/min/mg LDL, p < 0.01. Peroxidation was also evaluated from lipid peroxides (158 +/- 34 vs 57 +/- 18 nM/mg protein after LA, p < 0.05) and malonyldialdehyde (38 +/- 12 vs 27 +/- 8 nM/mg protein after LA, p < 0.05) content. When oxidized LDL was run on polyacrylamide gel extensive apo-B100 fragmentation was observed in LDL before LA, vs a less fragmentation after LA. A similar reduction was obtained in LDL agarose mobility after LA (1.7 +/- 0.2 vs 2.5 +/- 0.2, p < 0.05). Cholesterol esterification in mouse peritoneal macrophages was also decreased after LA (8.5 +/- 1.8 vs 14.6 +/- 2.7 nM/mg cell protein/12 hours, p < 0.05). Vitamin E content of LDL (mg/g protein) was increased after LA (4.44 +/- 1.0 vs 3.9 +/- 1.2, p < 0.05). Thus, selective LA, not only decreases the pool of LDL, but it also induces changes that render LDL less susceptible to oxidation and decreased high cholesterol esterification in macrophages. The prevention of these mechanisms by LA contributes actively to retard atherogenesis in HFH patients.
 ...
PMID:[LDL oxidation in homozygous familial hypercholesterolemia: effects of selective LDL-apheresis treatment]. 876 32

Both hyperinsulinemia and free oxygen radicals have been implicated in the pathogenesis of atherosclerosis, but the relationship between insulin levels or insulin action and the oxidant/antioxidant balance has not been explored. We measured the effect of physiologic hyperinsulinemia on plasma concentrations of vitamin E, a major free radical scavenger molecule. Isoglycemic clamps (at an insulin infusion rate of 6 pmol . min-1 . kg-1) were performed in four groups of subjects: (1) 12 non-insulin-dependent diabetic (NIDDM) patients, (2) eight patients with essential hypertension, (3) 11 nondiabetic obese individuals, and (4) 12 healthy subjects. In 10 healthy volunteers, a time-control experiment was performed by replacing the insulin infusion with normal saline. Vitamin E and plasma lipid levels were determined at baseline and after 2 hours of insulin/saline infusion. Insulin sensitivity was reduced in diabetic, obese, and hypertensive groups in comparison to healthy controls, but fasting plasma vitamin E concentrations were similar in all groups. A consistent decrement in plasma vitamin E concentrations (averaging 12% of baseline, P < .0001) was observed in all subjects receiving insulin regardless of the level of insulin sensitivity, whereas no significant changes in plasma vitamin E were seen in subjects receiving saline infusion (P < .001 v insulin infusion groups). The insulin-induced decrement persisted in all study groups when plasma vitamin E concentrations were corrected for total serum cholesterol levels (-8.9% +/- 1.2% v -0.4 +/- 2.3% of saline controls, P = .0004) or serum low-density lipoprotein (LDL(-10.0% +/- 1.2% v -0.4% +/- 2.2%, P = .0002). We conclude that insulin infusion acutely depletes vitamin E in circulating lipids regardless of insulin resistance. This effect may represent a physiologic means of transferring vitamin E into cell membranes; alternatively, it might reflect a pro-oxidant action of insulin in vivo.
 ...
PMID:Insulin decreases circulating vitamin E levels in humans. 876 59

Patients with homozygous familial hypercholesterolemia (FH), as a result of the increased levels and prolonged residence time of low density lipoprotein (LDL) in plasma, have a strong tendency toward accumulation of LDL-cholesterol in the arterial wall, causing premature atherosclerosis. This phenomenon may enhance per se the physiological degradation of both protein and lipid component of LDL, which be more susceptible to oxidative damage induced by oxygen radicals. It is well known that LDL may undergo oxidative modification before being taken up by macrophages which are then transformed into foam cells. It has been suggested that platelet-activating factor (PAF) may play an important role in atherogenesis and PAF catabolism is known to be mediated by serum acetylhydrolase, an enzyme that is normally associated with LDL. Thus, the present study was designed to investigate the structural properties of LDL, including acetylhydrolase activity, in homozygous FH as compared to normolipidemic subjects before and after xanthine/xanthine oxidase-mediated oxidation. We studied 8 homozygous FH patients matched with 8 normolipidemic volunteers. Lipids of LDL fraction were extracted and verified by thin layer chromatography (TLC) analysis. Fatty acids were methylated and injected into a gas chromatograph/mass spectrometer. Vitamin E in LDL was determined by high performance liquid chromatography (HPLC). As an index of susceptibility of LDL to oxidative modifications, the formation of lipid-conjugated dienes was continuously monitored at 234 nm. Lipid peroxidation was also evaluated from the amount of both lipid peroxides (LPO) and malonyldialdehyde (MDA) content. Apolipoprotein (apo) B-100 on LDL was carried on polyacrylamide and agarose gel electrophoresis. In the homozygous FH patients, the relative content of cholesteryl ester was slightly increased. Interestingly, the relative amount of arachidonic acid (20:4) was constantly increased in each lipid fraction in homozygous FH patients. The amount of vitamin E was not significantly different in the patient group from that in the control group. However, LDL from patients carried lower levels of vitamin E (nmol/mg LDL) than controls (2.7 +/- 0.4 vs. 2.9 +/- 0.3 P = NS). The results shows that lag time (min) was decreased (82 +/- 19 vs. 111 +/- 21; P < 0.05) and the maximal rate of diene production and total diene production was increased in homozygous FH patients. Mean levels of MDA were similar in both groups before oxidation, but levels after initiation of oxidation were significantly higher in the patient group. In contrast, mean levels of LPO were already higher in patients before oxidation (58 vs. 27 nmol/mg of protein; P < 0.05), and after initiation of oxidation were also significantly higher at each time points. When oxidized LDL was run on a polyacrylamide gel, an extensive apo B-100 fragmentation replaced by lower molecular mass fragments ranging from 45,000 to 205,000 m.wt., was observed only in LDL from homozygotes. Relative LDL agarose gel mobility shows that LDL from patients migrated higher than LDL of controls. Finally acetylhydrolase activity associated with LDL in patients was significantly reduced as compared to controls. Thus, in homozygous FH patients, LDL appeared more susceptible to oxidation in vitro; the indices for LDL oxidizability were all significantly different from those of controls. This phenomenon might be due to prolonged residence time of LDL in these patients, as suggested from high basal LPO levels and lower vitamin E levels carried by LDL. This hypothesis may explain together with the high content of arachidonic acid, the enhanced susceptibility of LDL from homozygous FH patients to oxidative damage.
Atherosclerosis 1995 Dec
PMID:Oxidative structural modifications of low density lipoprotein in homozygous familial hypercholesterolemia. 877 Mar 20

Vitamin E has been postulated to be antiatherogenic because of its antioxidative potency. However, intervention studies published to date have yielded conflicting results. To assess the antiatherogenic effect of vitamin E, two groups of 10 Watanabe heritable hyperlipidemic (WHHL) rabbits each were fed chow pellets containing D-alpha-tocopherol-acetate at either 40 mg/kg (control group) or 1000 mg/kg (vitamin E group) for 28 weeks. Plasma vitamin E levels in the vitamin E group increased five-fold over those controls (475.5 mumol/l vs. 95.9 mumol/l). The average total plasma cholesterol during the treatment period was not significantly affected by vitamin E (control, 950 +/- 113 mg/dl; vitamin E, 884 +/- 90 mg/dl). Vitamin E treatment had no significant effects on body weights, lipoprotein profiles, or HDL levels. The protection of plasma LDL against oxidation was determined by ex vivo by measuring the lag time in the formation of conjugated dienes in a standardized Cu22+(-)containing system. Lag time in the vitamin E-treated group increased four-fold over that in controls (404 vs. 123 min). The extent of atherosclerosis determined at the end of the study was not significantly different in the two groups (control group, 59.2 +/- 6.0%; vitamin E group, 50.6 +/- 6.2%, P = 0.33). Analysis of the correlation between vitamin E levels and extent of lesions also failed to indicate an antiatherosclerotic effect of vitamin E treatment. We previously reported that an analogue of probucol that provided antioxidative protection similar to that provided by vitamin E failed to prevent atherogenesis in WHHL-rabbits. In contrast probucol conveyed a much greater degree of antioxidant protection and effectively reduced atherosclerosis in rabbits. The results of the present study therefore support the hypothesis that a threshold level of antioxidative protection of LDL may be required to inhibit atherosclerosis.
Atherosclerosis 1995 Oct
PMID:Effect of vitamin E on atherogenesis in LDL receptor-deficient rabbits. 880 67

The cytotoxic effect of native high density lipoprotein (n-HDL) and oxidised high density lipoprotein (ox-HDL) on macrophages was studied and compared with that of low density lipoprotein (LDL). Copper-mediated oxidation of HDL and LDL was conducted in vitro and assessed by the analysis of conjugated dienes (CD). The kinetics of CD production during lipoprotein oxidation showed that HDL, relative to LDL, exhibited a shorter lag phase (47.7 +/- 17.8 vs. 82.9 +/- 24.5 min), higher diene production (242.2 +/- 23.0 vs 210.4 +/- 14.9 nmol/mg lipid) and reached maximal diene concentration in less time (100.0 +/- 35.4 vs 136.4 +/- 27.9 min). The maximal rate of CD production was 5.38 +/- 1.30 nmol/mg lipid/min for HDL and 4.42 +/- 0.60 nmol/mg lipid/min for LDL. Vitamin E concentration was higher in HDL than in LDL (2.76 +/- 0.41 vs. 2.19 +/- 0.33 micrograms alpha-tocopherol equivalent/mg lipid). Ox-HDL and oxidised LDL (ox-LDL), under the same experimental conditions, were cytotoxic to macrophages in a dose-dependent manner. At the same protein, or total mass concentration, ox-HDL was less cytotoxic than ox-LDL. However, when both lipoproteins were compared at the same lipid or cholesterol concentrations, ox-HDL was equally or more cytotoxic than ox-LDL. In conclusion, HDL is more susceptible to in vitro oxidation than LDL and the resultant modification of HDL converts this lipoprotein into a cytotoxic particle.
Atherosclerosis 1996 Aug 23
PMID:In vitro oxidised HDL exerts a cytotoxic effect on macrophages. 883 25

The authors studied the effect of vitamin E on endothelium-dependent coronary flow in hypercholesterolemic dogs. Adult mongrel dogs weighing 7.4 +/- 1.0 kg were divided into control, hypercholesterolemic and vitamin E groups. The animals in the hypercholesterolemic group were fed a diet enriched with cholesterol (5% w/w) and coconut oil (10% w/w) for 40 days. The vitamin E group received the same diet plus 400 IU of vitamin E during the last 15 days of the experiment. Total serum cholesterol levels were evaluated at the beginning and at the end of the experiment using a commercial enzyme kit and a Beckman analyzer. The coronary flow was determined by electromagnetic flowmetry using a probe positioned in the left anterior descending coronary artery, near the ostium. A needle connected to a perfusion pump was introduced into the coronary artery for the administration of acetylcholine and sodium nitroprusside at a rate of 5 micrograms/kg per min. The aorta was cannulated for the measurement of arterial blood pressure via a pressure transducer coupled to a Siemens multi-channel recorder. The tissue cholesterol content and malonic dialdehyde (MDA) were also measured in isolated coronary vessel specimens. At the end of 40 days, the serum cholesterol levels had increased by 226% and 190% in the hypercholesterolemic and vitamin E groups, respectively. However, the difference in the levels of these two groups was not significant (P > 0.05). The aortic blood pressure and heart rate remained unchanged during acetylcholine administration. In contrast, systolic and diastolic pressure fell and the heart rate increased during the infusion of sodium nitroprusside. The tissue cholesterol content and MDA were significantly (P < 0.05) increased in coronary artery specimens from the hypercholesterolemic compared to control animals. Vitamin E was able to reduce these increases in cholesterol treated animals (P < 0.05). The percent change in coronary flow during acetylcholine administration was significantly lower in the hypercholesterolemic group when compared with control animals (P < 0.05) but was unaltered in the vitamin E group (P > 0.05). During sodium nitroprusside administration, the coronary flow increased in the vitamin E group (P < 0.05). The authors conclude that hypercholesterolemia reduces endothelium-dependent coronary flow and increases the tissue cholesterol content and MDA of coronary arteries. Vitamin E decreases the MDA and the tissue cholesterol content without significantly affecting the total serum cholesterol level. Vitamin E may thus restore coronary flow by reverting endothelial dysfunction.
Atherosclerosis 1996 Sep 27
PMID:Effects of vitamin E on endothelium-dependent coronary flow in hypercholesterolemic dogs. 887 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>