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)

Findings in cell cultures, experimental animals, human lesions and human populations have, over the past decade, provided a new perspective of atherogenesis. Some of the more important findings are reviewed here. They permit the conclusion that atherosclerosis is a chronic inflammatory disease in which the activities of macrophages are responsible for the development of the lesion. The death of macrophages may be the cause of progression to advanced plaque. Only the advanced plaque causes the stenosis, thrombosis and ischaemia that are responsible for the fatal complications of the disease. There is evidence, as yet persuasive rather than conclusive, that lipid oxidation is an important mechanism in atherogenesis. If so, dietary supplementation with antioxidants such as vitamin E might be effective in postponing the development of the complications.
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PMID:The new face of atherosclerosis. 803 90

Despite a realisation that antioxidants will not delay ageing in healthy older people, there is increasing scientific interest in the role of free radical oxidants in a number of diseases associated with older age. For most of these diseases there is suggestive theoretical and laboratory evidence but not confirmatory clinical evidence. Free radical damage seems likely to be significant in the pathophysiology of atherosclerosis, ischaemia-reperfusion injury, Parkinson's disease, cataract, some cancers and rheumatoid arthritis. Evidence to suggest a protective effect from antioxidant vitamins exists for ischaemic heart disease, cataract and some cancers. Attempts to influence the outcome of other diseases such as ischaemia-reperfusion injury, Parkinson's disease and rheumatoid arthritis have so far failed to achieve positive results. Research interest in the field is increasing although hampered by methodological difficulties and the limited financial return for drug companies. In the meantime there seems no reason to discourage older people who wish to ingest extra vitamin E and vitamin C. A diet with adequate vegetables and fruits should provide sufficient beta carotene.
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PMID:Free radicals, antioxidants and preventive geriatrics. 806 Feb 75

Smokers incur a sustained free radical load that may increase their vitamin E requirement. Erythrocytes of male smokers from a Scottish population with a habitually low vitamin E intake were more susceptible to hydrogen peroxide-stimulated peroxidation than were those from nonsmokers (P < 0.001). Plasma concentrations of lipid peroxides, thiobarbituric acid reactive substances, and conjugated dienes were also elevated in smokers compared with nonsmokers (P < 0.05). These indexes of oxidative stress were markedly decreased (P < 0.001) in the smokers and nonsmokers after consumption of 280 mg dl-alpha tocopherol acetate/d for 10 wk. Platelet numbers in serum of both smokers and nonsmokers were also decreased by vitamin E supplementation (P < 0.02). Although the clinical significance of the results is unclear, elevated indexes of lipid peroxidation are associated with the pathogenesis of atherosclerosis, and platelets are involved with fibrinolysis. Therefore, both smokers and non-smokers may benefit from increased vitamin E intakes.
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PMID:Vitamin E supplementation suppresses indexes of lipid peroxidation and platelet counts in blood of smokers and nonsmokers but plasma lipoprotein concentrations remain unchanged. 807 69

The vascular effects of dietary vitamin E were investigated in isolated carotid artery preparations from cholesterol-fed New Zealand White rabbits. Rabbits were fed either a control, 1% cholesterol, or 1% cholesterol plus 0.2% vitamin E diet for 4 weeks. In raised-tone preparations, relaxant responses to acetylcholine were enhanced in rabbits fed cholesterol plus vitamin E, reversing the reduction in responses measured in preparations from cholesterol-fed rabbits. Relaxant responses to the calcium ionophore A23187 were significantly enhanced in cholesterol plus vitamin E-fed rabbits compared with those fed cholesterol alone, with no difference between control and cholesterol-fed rabbits. Relaxant responses to sodium nitroprusside were not different between the three dietary groups. Constrictor responses to noradrenaline and serotonin in isolated carotid artery preparations at basal tone were unaltered after cholesterol and cholesterol plus vitamin E diets. The copper-induced oxidation of beta-very-low-density lipoproteins (beta VLDL) isolated from plasma of rabbits fed a cholesterol plus vitamin E diet was almost completely inhibited compared with the oxidation of beta VLDL from rabbits fed cholesterol alone. These results show that vitamin E prevents endothelial dysfunction associated with cholesterol feeding and suggests that vitamin E may be beneficial in preventing functional impairment associated with atherosclerosis.
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PMID:Vitamin E protects against impairment of endothelium-mediated relaxations in cholesterol-fed rabbits. 812 58

Premature atherosclerosis and other vascular disorders are serious complications of diabetes mellitus. Contributing factors include (i) increased peroxidation of LDL leading to foam cell formation, fatty streaks and plaque formation in the arterial wall, and (ii) hyperreactivity of blood platelets leading to increased platelet adhesion and aggregation. Vitamin E may play a protective role as an antioxidant and/or membrane stabilizing agent in either mechanism. In platelets it appears to regulate arachidonic acid metabolism. Decreased vitamin E levels in platelets are associated with increased aggregation. This is reversible by correction of the vitamin E status. In diabetics, platelet vitamin E levels tend to be reduced with concomitant increase in platelet aggregation. Several studies in patients with insulin-dependent diabetes mellitus and, to some extent, in those with non-insulin-dependent diabetes mellitus have shown that supplementation with several hundred IU vitamin E significantly reduced platelet aggregation and lipid peroxidation. In healthy volunteers high-dose supplementation had no notable effect on platelet aggregation. However, doses as low as 200 IU vitamin E significantly reduced platelet adhesion and inhibited the formation of protruding pseudopods typically occurring in activated platelets. In diabetic patients a decrease in the nonenzymatic glycation of proteins by vitamin E supplementation has been observed. Controlled studies are needed to confirm the effect of vitamin E on platelet function in well-defined groups of diabetics, followed by large-scale trials investigating the prevention of diabetic vascular complications as clinical end point.
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PMID:Prevention of platelet dysfunction by vitamin E in diabetic atherosclerosis. 812 46

The vascular endothelium is the site of formation of several powerful mediators. One of these is NO, a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen. NO elicits relaxation of VSMC by activating cytosolic guanylate cyclase. NO also counteracts platelet adhesion and aggregation. The biological actions of NO make it a key substance in the endogenous defense against vascular occlusion and thrombosis. The basal formation of NO maintains a moderate but significant vasodilation in the systemic resistance vessels and counteracts platelet activity. When blood flow in conduit arteries is increased there is an augmented endothelial formation of NO, eliciting flow-dependent vasodilation. Beside this, several vasodilators (acetylcholine, bradykinin, histamine, substance P) operate by stimulating endothelial NO formation. On the other hand, drugs like nitroglycerin and papaverine operate independently of the vascular endothelium. Vasodilator mechanisms, physiological as well as pharmacological, may therefore be characterized as endothelium-dependent (i.e. NO-mediated), or endothelium-independent (i.e. not mediated by NO). Physiologically, mixed mechanisms occur. Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation, increased degradation, decreased sensitivity to the NO formed, or a mixture of these factors. Irrespective of the mechanism behind, this is referred to as endothelial dysfunction. Endothelial dysfunction occurs in several cardiovascular settings, like atherosclerosis, hypercholesterolaemia, diabetes, and essential hypertension. Endothelial dysfunction leads to an impaired tissue perfusion, increased local vascular resistance, decreased defense against thrombus formation, and possibly also decreased defense against hypertrophy of the VSMC in the vessel wall media. In patients with CHD, endothelial dysfunction leads to an impaired coronary flow response to physical and mental stress, and to promotion of platelet adherence and aggregability. Endothelial dysfunction is thereby a probable aggravating factor in the atherosclerotic process, adding a functional component on top of the structural lesions characterizing this disease. A particular form of endothelial dysfunction, limited to the arterial resistance vessels, may explain the symptoms and clinical characteristics of microvascular angina. In patients with essential hypertension, endothelial dysfunction prevails, adding a functional component to the structural factors also in this disease. Hitherto, the only therapeutic tools available to restore endothelial dysfunction appear to be restriction of the dietary intake of lipids, possibly reinforced with intake of antioxidants like fish oil and vitamin E. However, large clinical trials to confirm the efficacy of such therapy in reversing endothelial dysfunction have not been conducted. In the future, more directly acting therapeutic regimens, aimed at supporting or substituting the endogenous formation of NO, are likely to appear as well.
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PMID:Endothelial nitric oxide and cardiovascular disease. 815 Dec 63

Hypercholesterolemia attributable to increased plasma concentrations of low density lipoproteins is a well recognized risk factor for the premature development of coronary atherosclerosis in both experimental animals and humans. Recent studies have indicated that modifications to low density lipoprotein result in enhanced uptake of the modified lipoproteins by macrophages and lead to accelerated rates of lipid deposition and the creation of foam cells. Oxidation of low density lipoprotein has been shown to be one of the modifications which leads to uptake of this lipoprotein by scavenger receptors present on macrophages and results in intracellular lipid accumulation. Treatment of hypercholesterolemic animals with antioxidant drugs, including probucol, has been shown to reduce the development of atherosclerosis and xanthoma regression has been observed in patients with severe hypercholesterolemia treated with this drug. Epidemiologic studies support the view that low plasma concentrations of antioxidant vitamins, including vitamin E are associated with higher rates of coronary atherosclerosis in humans and that supplementation with vitamin E is associated with a decreased incidence of coronary artery disease. Prospective clinical trials to assess the potential benefit of antioxidant supplementation in high risk patients are currently in progress and these trials, when completed, should provide definitive information concerning the potential benefits to be derived from supplementation with antioxidant vitamins as an adjunctive therapy to prevent the premature development of atherosclerosis.
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PMID:The potential role of antioxidants in the prevention of atherosclerosis. 816 66

Antioxidants may be of use in the prevention of coronary artery disease by inhibiting low density lipoprotein (LDL) oxidation, a process that is believed to play an important role in atherogenesis. Because the structures of the 6- and 7-hydroxy-metabolites of doxazosin, an alpha 1-adrenergic-blocking antihypertensive agent, suggest that they might have antioxidant properties, studies were performed to determine whether these metabolites inhibit LDL oxidation. Micromolar concentrations of 6- and 7-hydroxydoxazosin, but not doxazosin itself, inhibited Cu(2+)-mediated oxidative modification of LDL in a dose-dependent fashion, similar to that observed with the lipophilic antioxidant, probucol. LDL modified in the presence of these metabolites was not taken up and degraded by macrophages to the same extent as LDL oxidized in their absence. In contrast to probucol, the antioxidant effect was lost after reisolation of LDL incubated with the metabolites. Whereas probucol, like vitamin E, sequesters with LDL, 3H-labeled 6- and 7-hydroxydoxazosin did not comigrate with lipoproteins on FPLC, but were associated with albumin and occurred free in solution. Thus, these metabolites of doxazosin may exert their antioxidant effect in the aqueous milieu of the lipoprotein, similar to vitamin C, and may be useful for the prevention of atherosclerosis in hypertensive individuals.
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PMID:Inhibition of low density lipoprotein oxidation in vitro by the 6- and 7-hydroxy-metabolites of doxazosin, an alpha 1-adrenergic antihypertensive agent. 817 51

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation and progression of the atherosclerotic plaque. After evaluation of a large number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidative modification induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric acid reactive substances returned to almost normal values in the presence of 0.5 microM of S 12340. Watanabe heritable hyperlipidemic rabbits were treated orally for 3 days or for 1 month with S 12340 to evaluate the potential protective effect of the compound on LDL oxidative modification induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to protect LDL in a dose-dependent manner and at doses as low as 10 mg/kg/day. Purified LDL from animals sacrificed at various times after oral administration of S 12340 were protected against oxidation for at least 6 h after the last administration of the compound. These findings are in good agreement with the plasma and LDL levels of S 12340 in these WHHL rabbits. S 12340, probucol and vitamin E were all able to decrease the optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demonstrating their free radical scavenging properties. The pharmacological properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.
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PMID:S 12340: a potent inhibitor of the oxidative modification of low-density lipoprotein in vitro and ex vivo in WHHL rabbits. 818 20

Oxidative stress is a metabolic state where the cellular oxidative reactions are out of control. Under such conditions superoxide (O2.-) may accumulate, leading to formation of the hydroxyl radical, OH.. This is a free radical that abstracts hydrogen from the double bonds of unsaturated fatty acids. The fatty acid will then become a free radical which reacts easily with oxygen to form a peroxyradical. This will in turn abstract hydrogen from another fatty acid, establishing a perpetuating oxidative chain reaction. This may lead to peroxidation of cellular functions. DNA, proteins and carbohydrates may be oxidized too. There is good evidence that oxidative stress may play a role in the pathogenesis of cancer, atherosclerosis, ischemic tissue damage and inflammatory diseases. Possibly antioxidants can be used to limit oxidative stress. Recent reports indicate that high intake of vitamin E is associated with reduced risk of coronary heart disease.
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PMID:[Oxidative stress and antioxidants]. 819 31


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