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

Abstract-cell-mediated lipoprotein oxidation may be due to generation of non-protein thiols (NP-SH) from cystine with formation of oxidizing species. However, NP-SH, especially GSH, may also exert antioxidant effects in vitro and in vivo. To further investigate whether vascular NP-SH could be prooxidants or antioxidants in atherosclerosis, we have correlated the aortic content of NP-SH with that of lipoperoxides in 10 rabbits fed on a fat-enriched atherogenic diet for 9 weeks. As compared to 7 control rabbits, aortic NP-SH and lipoperoxides were significantly increased in the fat-fed animals. The levels of NP-SH were strongly and inversely correlated with those of lipid peroxidation in the atherosclerotic aorta (r(s) -0.92, P < 0.0001 for thiobarbituric acid reactive substances, and r(s) -0.80, P < 0.01 for fluorescent damage products of lipid peroxidation). A similar trend was evident also in the control rabbits (r(s) -0.60 for both indices of lipid peroxidation). Thus, the present data suggest that vascular NP-SH exert significant antioxidant-antilipoperoxidative effects in vivo especially in fat diet-related atherogenic conditions.
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PMID:Vascular non-protein thiols: prooxidants or antioxidants in atherogenesis? 1063 Jun 72

In recent years it has been reported that free oxygen radicals play an important role in the pathogenesis of degenerative diseases and that antioxidant vitamins such as vitamins E or C prevent their harmful effects. In this study, we evaluated the following: Erythrocyte susceptibility to lipid peroxidation; the role of erythrocyte glutathione (GSH) as an antioxidant; plasma lipid fractions; and the relationship between plasma lipid peroxides and antioxidant vitamin levels. Thiobarbituric acid-reactive substance (TBARS) levels were measured to determine the levels of plasma lipid peroxides and the susceptibility to lipid peroxidation when erythrocytes were stressed by hydrogen peroxide for 2 h in vitro. Erythrocyte TBARS production was significantly higher in patients with coronary atherosclerosis than in the controls. On the other hand, the levels of plasma high-density lipoproteins, vitamin C, vitamin E and erythrocyte GSH were significantly lower, and the levels of plasma total cholesterol, triglycerides, low-density lipoproteins and TBARS were significantly higher in the patients with coronary atherosclerosis than in the controls. In conclusion, our results indicate that erythrocytes from patients with coronary atherosclerosis are more susceptible to oxidation than those of controls and that these patients have lowered antioxidant capacity as revealed by decreased plasma levels of vitamins C and E.
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PMID:Erythrocyte susceptibility to lipid peroxidation in patients with coronary atherosclerosis. 1063 80

Toxic effects of oxidized lipid compounds contained in oxidized LDL to endothelial cells are involved in the pathogenesis of atherosclerosis. Glutathione (GSH) plays an important role in the redox status of the cell and in the protective effect against oxidant injuries. However, little is known about the respective effect of these different oxidized lipid compounds toward cytotoxicity and GSH status of the cell. In this report, we isolated by high-performance liquid chromatography oxidized lipid compounds from low-density lipoproteins (LDL) oxidized by copper and we examined their effects on cultured endothelial cells. Cytotoxicity and GSH status were determined after incubation of endothelial cells with crude LDL or isolated lipid fractions derived from cholesterol, phospholipids, or cholesteryl esters. Their effects on cell morphology were also assessed. Oxidized lipids coming from cholesteryl esters (hydroperoxides or short-chain polar derivatives) induced a slight but significant GSH depletion without inducing cytotoxicity. The same species coming from phospholipids induced a more pronounced GSH depletion and a cytotoxic effect which is only present for the more polar compounds (short-chain polar derivatives) and corresponding to a total GSH depletion. In contrast, fractions containing oxysterols had a larger cytotoxic effect than their effect on GSH depletion suggesting that their cytotoxic effects are mediated by a GSH-independent pathway. All together, these data suggest that LDL-associated oxidized lipids present in copper-oxidized LDL exert cytotoxicity by an additional or synergistic effect on GSH depletion, but also by another mechanism independent of the redox status of the cell.
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PMID:In vitro study of the cytotoxicity of isolated oxidized lipid low-density lipoproteins fractions in human endothelial cells: relationship with the glutathione status and cell morphology. 1071 40

The need to investigate aminothiols such as glutathione (GSH), cysteine (Cys), and homocysteine (Hcy) in blood is stimulated by the current interest in hyperhomocysteinemia as a risk factor for atherosclerosis. Our current goal was to determine whether various cardiovascular (CV) diseases altered levels of GSH and Cys in blood and the relationships between these two thiols. Blood samples from 96 patients with atherosclerosis and other CV diseases were analyzed and compared with those from 33 control subjects. In CV patients, GSH levels were normal, but free plasma Cys was significantly higher (P < .0001). In patients with atherosclerosis, bound plasma Cys was 21% higher than that in control subjects (P < .0001), and in patients with other CV diseases it was 14% higher (P = .023). Also, in patients with CV diseases, correlations of free GSH with free Cys (P < .007) and total GSH and Cys with age (P < .04) differed from that in control subjects. There were no differences related to functional disability or duration of disease. A key finding was that these abnormal levels of plasma Cys occurred in both atherosclerotic and non-atherosclerotic CV diseases. These results indicate that high levels of oxidized and bound Cys in CV patients create an oxidative environment that may increase susceptibility to vascular damage.
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PMID:Blood glutathione and cysteine changes in cardiovascular disease. 1081 Oct 54

The objective of this study was to compare the effect of cholesterol feeding of rats and rabbits. The levels of lipid peroxidation products and oxysterols in the plasma of the two species plus the antioxidant enzyme activities in the liver and erythrocytes were measured to explain their different susceptibilities to atherosclerosis. Our study showed that rats are less susceptible than are rabbits to the atherogenic effect of a cholesterol-rich diet because of differences in lipid peroxidation products as well as antioxidant enzymes activities in their livers. In rabbits, cholesterol feeding produced severe hypercholesterolemia (43-fold increase) and increased plasma and liver lipid peroxidation. Total as well as the individual oxysterol contents of 7alpha-, 7beta-hydroxycholesterol, alpha-epoxy, beta-epoxycholesterol, cholestanetriol, 7-keto, and 27-hydroxycholesterol significantly increased in the plasma of hypercholesterolemic (HC) rabbits. Erythrocyte glutathione peroxidase (GSH-Px) activity significantly decreased whereas catalase activity significantly increased in HC rabbits. In rats cholesterol feeding increased the plasma cholesterol only twofold and had no effect on plasma or liver lipid peroxidation. Only 7alpha- and 7beta-hydroxycholesterol increased and no change was observed in any of the antioxidant enzymes activity in the erythrocytes. Although cholesterol feeding caused a 10-fold increase of liver cholesterol as ester in both rats and rabbits, the antioxidant enzyme GSH-Px and catalase activities in the liver significantly increased in rats but significantly decreased in rabbits. The increase of GSH-Px and catalase activities in the liver of cholesterol fed rats could have a protective role against oxidation, thus preventing the formation of lipid peroxidation and oxysterols.
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PMID:Cholesterol-rich diets have different effects on lipid peroxidation, cholesterol oxides, and antioxidant enzymes in rats and rabbits. 1087 4

The plasma reduced glutathione (GSH) selenoperoxidase is a highly conserved enzyme. Furthermore, a small clinical study reported that patients with severe atherosclerosis had low peroxidase activities. Together these observations suggest that the peroxidase is important in preventing atherosclerosis. Yet others have reported that when the assay was run in Tris buffer, it was inactive with the concentrations of GSH found in the plasma. Second, it is known that hyperhomocysteinemia increases the rate of atherogenesis. Because there is some homology between homocysteine and the cysteine in GSH, the question is whether the hyperhomocysteinemia effect may be due to inhibition of the peroxidase. We purified the peroxidase from human plasma and determined its activity by a coupled spectrophotometric assay and a substrate disappearance chemiluminescence assay. When the peroxidase activity was determined in phosphate-buffered saline solution (PBS), there was significant activity with the reported plasma GSH concentrations (5 to 20 micromol/L). The peroxidase was exclusively in the HDL fraction. There was no correlation between the peroxidase activity and the HDL or LDL cholesterol concentrations. Finally, at physiologic concentrations of GSH (9 micromol/L), the peroxidase was inhibited by physiologic, free homocysteine concentrations (1 to 5 micromol/L). These data suggest that the peroxidase is active in vivo and may be important in protecting the endothelium from atherosclerosis by preventing oxidant injury. The homocysteine inhibition of the peroxidase suggests a possible biochemical basis for the observed association between hyperhomocysteinemia and cardiovascular disease. Our studies imply that low concentrations of this peroxidase may be an independent risk factor for atherosclerosis.
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PMID:Physiologic concentrations of homocysteine inhibit the human plasma GSH peroxidase that reduces organic hydroperoxides. 1088 28

Polysaccharide krestin (PSK) is a protein-bound polysaccharide extracted from the sporophore Coriolus versicolor. Previously, we found that PSK could reduce the oxidative injury that oxidised low-density lipoprotein (Ox-LDL) produced in monocytes/macrophages, and therefore have some pro-phylactic or therapeutic effect on atherosclerosis. Glutathione peroxidases, including selenium-dependent glutathione peroxidase (SeGPx) and non-selenium-dependent glutathione peroxidase (non-SeGPx, also called glutathione S-transferase [GST]), play an important role in the defence against oxidative injury. In order to find out if the effects of PSK were associated with antioxidant enzymes, we investigated its effect on glutathione peroxidase activity and messenger RNA (mRNA) expression in mouse peritoneal macrophages. Results showed that PSK enhanced SeGPx and non-SeGPx activity, and increased SeGPx and GST-P (pi class GST) mRNA in mouse peritoneal macrophages. In addition, the induction by PSK of the two glutathione peroxidases could be blocked by cycloheximide (30 micrograms/mL), but 5 micrograms/mL actinomycin D and 50 micrograms/mL acetovanilone (a superoxide inhibitor) had no effect. We conclude that PSK improved glutathione peroxidase activity through transcriptional induction of mRNA expression.
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PMID:Effect of polysaccharide krestin on glutathione peroxidase gene expression in mouse peritoneal macrophages. 1091 87

The effects of a high-cholesterol diet in the presence and absence of defibrotide, a single-stranded polydeoxyribonucleotide compound, on the lipid peroxidation product malondialdehyde, endogenous antioxidant enzymes catalase, glutathione peroxidase, and the antioxidant thiol compound GSH were investigated. Forty male New Zeland white rabbits were divided into four groups each consisting of 10 rabbits. Group I received a regular rabbit chow diet and group II 1% cholesterol plus regular chow, group III was given defibrotide (60 mg/kg per day p.o. in water) and was fed with regular chow, and group IV received defibrotide plus 1% cholesterol for 9 weeks. Blood cholesterol and malondialdehyde, catalase, glutathione peroxidase, and GSH were determined before starting the experimental diet regimen (basal). After 9 weeks, the same parameters were determined in blood, aorta, and brain tissues (end -experiment). Aortic tissue was examined under a light microscope for morphological alterations indicative of atherosclerosis. The increase in serum total cholesterol was greater in group II than group IV. Plasma malondialdehyde in group II was higher than in group III. Brain malondialdehyde in group II was higher than all other groups, and aortic malondialdehyde in this group was higher than group I and III. Serum catalase activity decreased in group II and increased in group III, compared with basal values. Brain catalase activity in group I was higher than group II, and aorta catalase in group IV was higher than in group I and III. Blood glutathione peroxidase activity in group III and IV was higher than basal. GSH concentrations decreased significantly in the cholesterol-fed groups (group II and IV). Histological alterations in the cholesterol-fed groups were more pronounced in group II. The increased levels of malondialdehyde in plasma, aorta, and brain tissue of group II suggest a role of oxygen free radicals in the pathogenesis of cholesterol-induced atherosclerosis. The higher malondialdehyde values in the brain tissues of animals in group II compared with group IV suggest a protective role of defibrotide in the brain against lipid peroxidation in the oxidant stress of cholesterol-induced atherosclerosis. Increased catalase activities in the blood and aortic tissues and increased glutathione peroxidase activities in the blood of rabbits receiving defibrotide suggest an induction of these antioxidant enzyme activities by defibrotide. These results imply that anti-atherosclerotic, anti-ischemic effects of this drug may be due to the beneficial effects on the oxidant-antioxidant balance of various tissues.
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PMID:Effects of defibrotide on aorta and brain malondialdehyde and antioxidants in cholesterol-induced atherosclerotic rabbits. 1104 4

Elderly humans have altered cellular redox levels and dysregulated immune responses, both of which are key events underlying the progression of chronic degenerative diseases of ageing, such as atherosclerosis and Alzeimer's disease. Poorly maintained cellular redox levels lead to elevated activation of nuclear transcription factors such as NFkB and AP-1. These factors are co-ordinately responsible for a huge range of extracellular signalling molecules responsible for inflammation, tissue remodelling, oncogenesis and apoptosis, progessess that orchestrate many of the degenerative processess associated with ageing. It is now clear that levels of endogenous anti-oxidants such as GSH decrease with age. This study aimed to investigate the potential of exogenous anti-oxidants to influence inflammatory responses and the ageing process itself. We investigated the potential of the dietary antioxidant, quercetin, to reverse the age related influences of GSH depletion and oxidative stress using in vitro human umbilical vein endothelial cells (HUVEC) and human skin fibroblast (HSF) cell models. Oxidative stress-induced inflammatory responses were investigated in a GSH depletion and a Phorbol 12-myristate 13-acetate (PMA)-induced stress model. As measured with a sensitive HPLC fluorescence method, GSH in HUVEC was depleted by the addition of L-buthionine-[S,R]-sulfoxiniine (BSO), a gamma-glutamylcysteine synthetase inhibitor, to the culture medium at a concentration of 0.25 mM. Time course studies revealed that the GSH half-life was 4.6 h in HUVEC. GSH depletion by BSO for 24 h led to a slight increase in intracellular adhesion molecule - 1 (ICAM1) expression and prostaglandin E2 (PGE2) secretion in both types of cells. However, GSH depletion markedly enhanced PMA-induced ICAM and PGE2 production in HUVEC. Responses were progressively elevated following prolonged BSO treatment. Inhibition studies showed that 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7), a protein kinase C (PKC) inhibitor, not only abolished most of PMA-induced ICAM-1 expression and PGE2, production, but also eliminated GSH depletion-enhanced PMA stimulation. This enhancement was also inhibited by supplementation with quercetin. The results clearly demonstrate that GSH depletion increased the susceptibility of vascular endothelial cells and fibroblasts to oxidative stress associated inflammatory stimuli. This increased in vitro susceptibility may be extrapolated to the in vivo situation of ageing, providing a useful model to study the influence of micronutrients on the ageing process. In conclusion, these data suggest that dietary antioxidants could play a significant role in the reduction of inflammatory responses.
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PMID:Antioxidants may contribute in the fight against ageing: an in vitro model. 1116 75

Several studies have suggested that the oxidative modification of low-density lipoprotein (LDL) could play a key role in the early stages of atherosclerosis. The susceptibility of LDL to oxidation has been found to be greater in patients with coronary heart disease. Familial hypercholesterolaemia (FH) is a powerful clinical model in which to study the predictive role of LDL in atherogenesis. LDL-apheresis is a treatment that is able to decrease lipid levels in plasma. This study was aimed at investigating the reducing capacity of erythrocytes and the in vitro susceptibility to oxidation of LDL isolated from patients with homozygous, heterozygous and double-heterozygous FH, who were treated fortnightly with LDL-apheresis or left untreated. In 14 FH patients, at baseline and after a cycle of treatment, the susceptibility of LDL to oxidative modification was analysed by studying the kinetics of conjugate diene formation. Plasma hydroperoxides, polyunsaturated fatty acid content, LDL electrophoretic mobility on agarose, the titre of auto-antibodies against oxidized LDL and serum paraoxonase activity were also measured. Furthermore, in order to evaluate a potential relationship between LDL oxidation and redox status, erythrocyte GSH and ATP levels were determined in FH patients treated regularly or never treated previously by LDL-apheresis. Unlike in the control group, the oxidative status of LDL in all FH patients was modified by LDL-apheresis, as revealed by the higher negative charge and the increase in levels of hydroperoxides and antibodies against oxidized LDL in the plasma. Our findings suggest both an acute effect and a long-term effect of LDL-apheresis in FH patients treated with dextran sulphate cellulose apheresis. The acute effect of LDL-apheresis on the susceptibility to oxidation of plasma and LDL was demonstrated by significant decreases in plasma hydroperoxide content, total LDL concentration and polyunsaturated fatty acid content. The increased resistance of LDL to oxidation was shown by prolongation of the lag time (P<0.05) in samples after a single cycle of treatment. The long-term effect of LDL-apheresis was demonstrated by the comparable values for lag phases (obtained from the kinetics of conjugate diene formation) in patients under active treatment and controls. Compared with healthy controls and untreated patients, the erythrocyte GSH content was significantly higher (P</=0.001) in the treated group, suggesting the activation of reducing mechanisms.
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PMID:Acute and long-term effects of low-density lipoprotein (LDL)-apheresis on oxidative damage to LDL and reducing capacity of erythrocytes in patients with severe familial hypercholesterolaemia. 1117 Dec 88


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