UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative modification converts low-density lipoprotein (LDL) into its atherogenic form and appears to be a necessary precondition for LDL uptake by macrophages during foam cell formation. Cellular lipoxygenases have been implicated in this process. We studied the interaction of purified mammalian lipoxygenases with human LDL in vitro and found that the arachidonate 15-lipoxygenases of rabbit and man are capable of oxygenating lipoproteins as indicated by oxygen uptake and by the formation of thiobarbituric-acid-reactive substances. Furthermore, oxygenated polyenoic fatty acids, such as 13-hydro(pero)xy-9Z,11E-octadecadienoic acid and 15-hydro(pero)xy-5,8,11,13(Z,Z,Z,E)-eicosatetraenoic acid were detected in the lipid compartment of various lipoproteins classes after lipoxygenase treatment. More than 90% of the oxygenated polyenoic fatty acids were found in the ester-lipid fraction, particularly in the cholesterol esters, whereas only small amounts of free hydro(pero)xy polyenoic fatty acids were detected. Lipoxygenase-catalyzed oxygenation of LDL is not restricted to the lipid compartment but also leads to a cooxidative modification of the apoproteins as indicated by changes in the electrophoretic mobility and by the formation of carbonyl derivatives of amino acid side chains. The possible biological significance of lipoxygenase-induced oxidative modification of lipoproteins in the pathogenesis of atherosclerosis is discussed.
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PMID:Oxygenation of lipoproteins by mammalian lipoxygenases. 847 99

The lipoxygenase (LO) pathway of arachidonate metabolism has been suggested to play a key role in atherosclerosis and in mediating several actions of angiotensin II (AII). However, the relationship between LO activation and factors linked to accelerated diabetic vascular disease such as hyperglycemia and AII is not known. We have investigated the effect of high glucose (HG; 25 mM) and AII on LO activity as well as LO protein and mRNA expression in porcine aortic vascular smooth muscle cells (PVSMCs). We observed that cells cultured in HG had significantly higher levels of the cell-associated LO products 12- and 15-hydroxyeicosatetraenoic acids (HETEs). AII added to cells grown in HG specifically further increased only cell-associated 12-HETE levels. Using immunoblot analysis and reverse transcriptase PCRs, we demonstrated the presence in PVSMCs of porcine leukocyte-type 12-LO protein and mRNA, respectively. Furthermore, the levels of both were markedly upregulated by AII as well as by HG. These studies suggest that enhanced 12-LO activity and expression are mechanisms for accelerated vascular disease produced by HG and AII in diabetes mellitus.
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PMID:Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells. 850 39

Oxidative modification of low-density lipoprotein (LDL) has been implicated in foam-cell formation at all stages of atherosclerosis. Since transition metals and mammalian 15-lipoxygenases are capable of oxidizing LDL to its atherogenic form, a concerted action of these two catalysts in atherogenesis has been suggested. Cu2+-catalysed LDL oxidation is characterized by a kinetic lag period in which the lipophilic antioxidants are decomposed and by a complex mixture of unspecific oxidation products. We investigated the kinetics of the 15-lipoxygenase-catalysed oxygenation of LDL and found that the enzyme is capable of oxidizing LDL in the presence of the endogenous lipophilic antioxidants. In contrast with the Cu2+-catalysed reaction, no kinetic lag phase was detected. The pattern of products formed during short-term incubations was highly specific, with cholesterol-esterified (13S)-hydroperoxy-(9Z,11E)-octadecadinoic acid being the major product. However, after long-term incubations the product pattern was less specific. Preincubation with 15-lipoxygenase rendered human LDL more susceptible to Cu2+-catalysed oxidation as indicated by a dramatic shortening of the lag period. Addition of Cu2+ to lipoxygenase-treated LDL led to a steep decline in its antioxidant content and to a greatly reduced lag period. Interestingly, if normalized to a comparable hydroperoxide content, autoxidation and addition of exogenous hydroperoxy fatty acids both failed to overcome the lag period. The local peroxide concentrations in various LDL subcompartments will be discussed as a possible reason for this unexpected behaviour.
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PMID:Lipoxygenase treatment render low-density lipoprotein susceptible to Cu2+-catalysed oxidation. 867 73

This article reviews our current understanding of the mechanisms of low-density lipoprotein (LDL) oxidation and the potential role of oxidized lipoproteins in atherosclerosis. Studies in hypercholesterolemic animal models indicate that oxidation of LDL is likely to play an important role in atherogenesis. Epidemiological investigations further suggest that the dietary intake of antioxidants is inversely associated with the risk of vascular disease, suggesting that oxidized LDL may be important in human atherosclerosis. By activating inflammatory events, oxidized lipoproteins may contribute to all stages of the atherosclerotic process. Lipoprotein oxidation is promoted by several different systems in vitro, including free and protein-bound metal ions, thiols, reactive oxygen intermediates, lipoxygenase, peroxynitrite, and myeloperoxidase. Intracellular proteins that bind iron or regulate iron metabolism might also play an important role. The physiologically relevant pathways have yet to be identified, however. We assess recent findings on the effects of antioxidants in vivo and suggest potential strategies for inhibiting oxidation in the vessel wall.
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PMID:The role of oxidized lipoproteins in atherogenesis. 872 15

Arachidonic acid elicited relaxation responses in normal rabbit aorta precontracted with norepinephrine. The relaxation response was enhanced by the cyclooxygenase inhibitor indomethacin and inhibited by lipoxygenase inhibitors, including nordihydroguaiaretic acid and cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. The cytochrome P-450 epoxygenase inhibitor metyrapone had no effect on arachidonic acid-induced relaxations. The present study hypothesized that a lipoxygenase metabolite of arachidonic acid mediated the response. Incubation of rabbit aorta with [14C]arachidonic acid resulted in the synthesis of a previously unidentified 14C-labeled metabolite and was called the unknown factor. Production of the unknown factor was not inhibited by indomethacin and decreased by lipoxygenase inhibitors. Production of the unknown factor and arachidonic acid-induced relaxations were dependent on an intact endothelium, indicating that the cellular source of the unknown relaxant factor was the endothelial cell. This was confirmed by demonstrating the ability of cultured rabbit aortic endothelial cells to produce the unknown factor from [14C]arachidonic acid. Feeding rabbits a 2% cholesterol diet for 2 wk induced hypercholesterolemia without causing atherosclerosis. In the cholesterol-fed rabbits, indomethacin enhanced arachidonic acid-induced relaxations in norepinephrine-precontracted aortas (maximal relaxation 49.0 +/- 2.5 vs. 35.5 +/- 1.7%, cholesterol-fed vs. normal) and increased production of the unknown factor compared with normal rabbits. The partially purified unknown factor elicited an approximately 26% inhibition of the vasoconstrictor response to norepinephrine in intact rabbit aorta. Further purification of the unknown factor by reverse-phase high-pressure liquid chromatography system resulted in isolation of a radioactive product that relaxed precontracted rabbit aorta. Therefore these data suggest that in normal and hypercholesterolemic rabbit aorta the endothelium produces an unknown metabolite of arachidonic acid that causes vasorelaxation and may regulate vascular tone.
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PMID:Vasorelaxation by an endothelium-derived metabolite of arachidonic acid. 878 Jan 99

To test the hypothesis that red wine, by virtue of its relatively high concentration of polyphenols, is more protective against atherosclerosis and coronary heart disease (CHD) than white wine, and that grape juice enriched in one of these, trans-resveratrol, may share some of these properties, studies were performed on 24 healthy males aged 26-45 years. Each consumed the following beverages for periods of 4 weeks: red wine, white wine, commercial grape juice and the same grape juice enriched with trans-resveratrol. Apart from the last beverage, 2 weeks abstinence was maintained before commencing the schedule. Blood was taken at the beginning and end of each schedule to determine plasma thromboxane B2 (TxB2) concentration and the IC50 (concentration required for 50% aggregation) for ADP and thrombin-induced platelet aggregation. White wine (P < 0.05) but not red wine increased the IC50 for ADP. Both wines increased the IC50 for thrombin (P < 0.02 and P < 0.001, respectively) and also lowered plasma TxB2 concentrations (P < 0.01 and P < 0.025, respectively). Neither grape juice altered ADP-induced aggregation or TxB2 concentrations, but the commercial juice lowered the IC50 for thrombin (P < 0.001) whereas the resveratrol-enriched juice caused a dramatic increase (P < 0.001). In vitro experiments demonstrated that the aggregation of fresh washed human platelets by ADP and thrombin was moderately reduced by both grape juices, strongly by red wine and not at all by white wine. The synthesis of TxB2 by platelets from labelled arachidonate was stimulated by commercial grape juice, slightly enhanced by resveratrol-enriched juice and strongly inhibited by red wine with white wine having little effect. Platelets from subjects consuming the commercial juice had a higher ratio of cyclo-oxygenase to lipoxygenase product formation and those consuming the resveratrol-enriched juice a lower ratio than during the control period. We conclude that trans-resveratrol can be absorbed from grape juice in biologically active quantities and in amounts that are likely to cause reduction in the risk of atherosclerosis. The failure of red wines (which have a 20-fold excess of polyphenols over white wines) to show any advantage suggests that, in vivo, ethanol is the dominant anti-aggregatory component in these beverages which are more potent than grape juices in preventing platelet aggregation in humans.
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PMID:Wines and grape juices as modulators of platelet aggregation in healthy human subjects. 881 65

The lipoxygenase product 15-hydroxyeicosatetraenoic acid (15-HETE) was shown to be the most important eicosanoid formed in the atherosclerotic rabbit aorta. The aim of the present study was to compare the effects of 15-HETE and its hydroperoxy precursor 15-HpETE with those of other vasoconstrictor and vasodilator agents in arteries from rabbits fed either a control or a cholesterol-rich diet for 16 and 30 weeks. 5-Hydroxytryptamine (5-HT) aggregated platelets and thrombin caused contractions of isolated rabbit aortas. The contractile responses elicited by platelets from control animals were similar to those evoked by platelets from atherosclerotic rabbits. After 16 weeks of hypercholesterolemia, the contractile responses were either augmented (5-HT), unchanged (platelets) or reduced (thrombin). After 30 weeks of hypercholesterolemia, the responses to all contractile agents used had decreased. In both aortas and pulmonary arteries the endothelium-dependent relaxations to the calcium ionophore, A23167, and to acetylcholine were progressively lost and the endothelium-independent relaxations to nitroglycerin were reduced by the progressing hypercholesterolemia. The 15-lipoxygenase metabolites contracted the isolated thoracic aorta and pulmonary artery from control rabbits and to a lesser extent those of the cholesterol-fed rabbits. After raising the tone in these vessels with prostaglandin F2 alpha PGF2 alpha) or noradrenaline, 15-HpETE induced relaxations which were not significantly influenced by the development of fatty streaks. Our data illustrate that the contractions of the blood vessel wall to 15-HETE, like those to other vasoconstrictors, are markedly reduced by developing atherosclerosis. In contrast, the relaxations to 15-HpETE in the rabbit arteries remain unaltered after 16 to 30 weeks of hypercholesterolemia. This is unlike the reactions to other vasodilators, which are markedly reduced.
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PMID:Influence of hypercholesterolaemia on the reactivity of isolated rabbit arteries to 15-lipoxygenase metabolites of arachidonic acid: comparison with platelet-derived agents and vasodilators. 884 33

In the last five years, there has been a renewal of interest in the protective role of selenium in vascular disorders, inspired by experimental evidence that this trace element could modulate leukotriene and prostaglandin synthesis in both endothelial cells and platelets. In people living in low-selenium areas, a relationship has been established between a decrease in plasma selenium and an increase in the risk of coronary disease, atherosclerosis, platelet hyperaggregability and synthesis of proaggregant and proinflammatory compounds like thromboxane A2 and leukotrienes. Selenium, as an essential part of glutathione peroxidase, takes part in the reduction of hydrogen peroxides and lipid peroxides. The concentration of these peroxides, in turn, regulates the activities of cyclooxygenase and lipooxygenase pathways, ultimately influencing the production of eicosanoids and modulating the balance between a proaggregatory and antiaggregatory state. Recent evidence shows that selenium, via its action on glutathione peroxidase activity, may be primarily responsible for the regulation of the endogenous hydroperoxide level. In human platelets, the activity of glutathione peroxidase is particularly high and is very sensitive to the requirement of selenium. This sensitivity could explain why platelets of selenium-deficient subjects show increased aggregation, thromboxane B2 production and synthesis of the lipoxygenase-derived compounds. In these deficient subjects, selenium administration increases platelet glutathione peroxidase activity and inhibits platelet hyperaggregation and leukotriene synthesis. These results support the hypothesis that selenium supplementation has a positive effect on platelet aggregation in selenium-deficient subjects. In France, more than 10% of the population is selenium-deficient and long-term supplementation with low doses of selenium could have a beneficial effect on the prevention of both thrombosis and coronary heart disease in these subjects.
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PMID:[Selenium, glutathione peroxidase, peroxides and platelet functions]. 886 57

Cellular oxidation of protein and lipoproteins is believed to contribute to the pathology associated with both acute and chronic inflammatory processes. Enzymatic, myeloperoxidase and lipoxygenase, and non- enzymatic oxidation of low density lipoprotein, LDL, has been implicated in foam cell formation and the progression of atherosclerotic changes within the arterial wall. In the present study, the in vitro protective role of the selective estrogen receptor modulator, raloxifene, in these oxidant triggered processes has been investigated. Raloxifene, as with estrogen was observed to inhibit both copper mediated LDL oxidation as well as the cellular modification of LDL by murine peritoneal macrophages. Raloxifene was, however, a more potent inhibitor of LDL oxidation than 17 beta-estradiol. The inhibition of macrophage LDL modification by raloxifene was not due to a non-specific effect on all effector functions as phagocytosis of opsonized yeast was comparable with control macrophage cultures. In addition to the protective effects on LDL oxidation, raloxifene also inhibited tyrosyl radical formation catalyzed by myeloperoxidase. The inhibition of myeloperoxidase activity was observed for both the isolated enzyme and in phorbol ester stimulated murine peritoneal neutrophils. In contrast, raloxifene was a weaker inhibitor of horseradish peroxidase. These results demonstrate a potential protective role for raloxifene as an anti-oxidant in in vitro assays designed to evaluate oxidant mediated radical formation and tissue damage.
Atherosclerosis 1996 Sep 27
PMID:Inhibition of LDL oxidation and myeloperoxidase dependent tyrosyl radical formation by the selective estrogen receptor modulator raloxifene (LY139481 HCL). 887 35

It is postulated that cell injury activates "dormant" enzymes to produce lipid hydroperoxides. In a first step, membrane lipids are cleaved by esterases. The unsaturated fatty acids thus produced are converted in a second step by lipoxygenases to lipid hydroperoxides (LOOHs). In a third, nonenzymic step, these LOOHs, together with dienoic hydroxy fatty acids produced by enzymic reduction of LOOHs, react with a second oxygen molecule to generate dihydroperoxy-fatty acids and hydroxy-hydroperoxy-fatty acids, which are degraded to alpha-hydroxyladehydic compounds. This last reaction requires production of LO'-radicals by iron ions that also are generated as a result of cell damage. In addition, alpha-hydroxyaldehydes are produced by hydrolysis of plasmalogen epoxides, which are generated by oxidation of plasmalogens with LOO' or by action of epoxidases. We hypothize that alpha-hydroxyaldehydes act as second messengers. The release of lipoxygenase and the consequent lipid hydroperoxidation is postulated to occur in massive cell damage (e.g., myocardial infarction), in chronic diseases such as rheumatism, diabetes and atherosclerosis, in aging, and in control of cell proliferation.
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PMID:Enzymic lipid peroxidation--a consequence of cell injury? 893 85

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