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)

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

Macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherosclerosis, is the result of enhanced cellular uptake of plasma low density lipoprotein (LDL). Native LDL, has to undergo oxidative modifications in order to be taken up at an enhanced rate by macrophages, leading to foam cell formation. Macrophage uptake of oxidized LDL involves its binding to scavanger receptors (including cellular proteoglycans) and this is followed by an impaired cellular cholesterol metabolism. Cells of the arterial wall including macrophages can oxidize LDL in a process that involves activation of cellular oxygenases, such as NADPH oxidase and 15-lipoxygenase. This process, however, also depends on the macrophage antioxidant environment, where glutathione peroxidase and reduced glutathione play an important protective role against cell-mediated oxidation of LDL. Macrophage phospholipids peroxidation under oxidative stress can also contribute to macrophage-mediated oxidation of LDL. Evidence for the occurrence of oxidized LDL in vivo is as follows: 1) In the atherosclerotic lesion [in humans, as well as in the transgenic, apolipoprotein E-deficient mice], LDL is oxidized (and as a result, it is also aggregated), in comparison to plasma LDL which is normally not oxidized. 2) Plasma LDL from patients at high risk for atherosclerosis (such as hypercholesterolaemic, hypertensive, diabetic and renal failure patients), as well as from the apolipoprotein E-deficient mice, demonstrates increased susceptibility to oxidation in comparison to normal LDL. In some groups of these patients LDL is minimally oxidized already in plasma. 3) Supplementation of nutritional antioxidants, which are rich in polyphenols (red wine, licorice, olive oil), or of selenium to humans or to the apolipoprotein E-deficient mice, as well as therapy with beta-hydroxy-beta-methyl-glutaryl-CoA reductase inhibitors (so-called "statins") in hyperocholesterolaemic patients, were shown to reduce the susceptibility of LDL to oxidation. This effect could be associated with a reduction in the size of the atherosclerotic lesion and may thus contribute to attenuation of the atherosclerotic process.
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PMID:Interaction of oxidized low density lipoprotein with macrophages in atherosclerosis, and the antiatherogenicity of antioxidants. 887 34

Oxidative modification of LDL increases its atherogenicity, and 15-lipoxygenase (15-LO) has been implicated in the process. To address this issue, we generated transgenic rabbits that expressed 15-LO in a macrophage-specific manner and studied their susceptibility to atherosclerosis development when they were fed a high-fat, high-cholesterol (HFHC) diet (Teklad 0533 rabbit diet 7009 with 10% corn oil and 0.25% cholesterol) for 13.5 wk. Transgenic and nontransgenic rabbits developed similar degrees of hypercholesterolemia and had similar levels of triglyceride, VLDL, LDL, and HDL. Quantitative morphometric analysis of the aortic atherosclerosis indicated that the transgenic animals (n = 19) had significantly smaller lesion areas (9.8+/-6.5%, mean+/-SD) than their littermate controls (n = 14, 17.8+/-15.0%) (P < 0.05). In a subgroup (n = 9) of transgenic rabbits that received the HFHC diet plus the antioxidant N',N '-diphenyl-phenylenediamine (1%), the extent of lesion involvement (9.8+/-7.5%) did not differ from the subgroup (n = 10) that received the regular HFHC diet (9.7+/-5.9%). Since the results were unexpected, we repeated the experiments. Again, we found that the nontransgenic littermates (n = 12) had more extensive lesions (11.6+/-10.6%) than the transgenic rabbits (n = 13; 9.5+/-7.8%), although the difference was not significant. In a third set of experiments, we crossed 15-LO transgenic rabbits with Watanabe heritable hyperlipidemic (WHHL) rabbits and found that the lesion area in the 15-LO transgenic/heterozygous WHHL rabbits (n = 14) was only about one third (7.7+/-5.7%) that found in nontransgenic heterozygous WHHL littermate controls (n = 11, 20.7+/-19.4%) (P < 0.05). These data suggest that overexpression of 15-LO in monocytes/macrophages protects against lipid deposition in the vessel wall during early atherogenesis in these rabbit models of atherosclerosis.
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PMID:Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. 894 35

Mammalian lipoxygenases are implicated in the biosynthesis of inflammatory mediators, in the pathogenesis of atherosclerosis and in the process of blood cell differentiation and maturation. With respect to their reaction specificity, three major types of mammalian lipoxygenases (15-lipoxygenases, 12-lipoxygenases and 5-lipoxygenases) may be classified. Although this nomenclature is commonly used, the mechanistic reasons for the positional specificity of lipoxygenases are not well understood. We investigated the structural reasons for lipoxygenase specificity by a combination of chimera formation and site-directed mutagenesis, and identified phenylalanine 353 as primary determinant for the positional specificity of rabbit reticulocyte 15-lipoxygenase. Modeling of the enzyme-substrate interaction suggested that the alignment of arachidonic acid at the active site appears to be influenced by this residue. According to the substrate orientation, the 15-lipoxygenase may be differentiated from two types of mammalian 12-lipoxygenases.
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PMID:Phenylalanine 353 is a primary determinant for the positional specificity of mammalian 15-lipoxygenases. 900 Jun 36

Oxidative modification of low density lipoprotein has been suggested as patho-physiologically relevant process in atherogenesis and the lipid peroxidizing enzyme 15-lipoxygenase may be involved. For experimental evidence on the in vivo action of this enzyme in the time course of plaque formation we analyzed the lipid extracts of lesional areas representing various stages of human atherogenesis for the occurrence of specific 15-lipoxygenase products. In advanced human lesions the degree of oxygenation of the lesion lipids measured as hydroxy linoleic acid/linoleic acid ratio varied between 0.2 and 3.2%. Here an unspecific pattern of oxygenated lipids that did not differ from the pattern formed during copper-catalyzed LDL oxidation was detected. In both cases an enantiomer ratio (S/R-ratio) of 13-hydroxy-9Z,11E-octadecadienoic acid (13-HODE) of approximately 1:1 was found. In young human lesions which were obtained from the collection of the pathological determinants of atherosclerosis in youth (PDAY) program the hydroxy linoleic acid/linoleic acid ratio was much smaller (variation between 0.05 and 0.6%), and a significant share of specific 15-lipoxygenase products was detected (S/R-ratio of 13-hydroxy linoleic acid of 54 +/- 3.1/46 +/- 3.1 [mean +/- SD]). These data suggest that the 15-lipoxygenase is enzymatically active on endogenous substrates in young human lesions and thus, may be of patho-physiological importance for early atherogenesis. In advanced human plaques the 15-lipoxygenase may be functionally silent and specific lipoxygenase products formed in earlier stages may be decomposed or superimposed by large amounts of nonenzymatic lipid peroxidation products.
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PMID:In vivo action of 15-lipoxygenase in early stages of human atherogenesis. 906 46

15-lipoxygenase is a lipid-peroxidating enzyme that oxidizes fatty acids, such as those esterified to cellular membranes. It has been implicated in the oxidative modification of low-density lipoprotein and is thus thought to contribute to the development of atherosclerosis. The enzyme has also been shown to be specifically induced by interleukin-4 in human blood monocytes. Two 15-lipoxygenase-hybridizing messages were detected in these cells; one (2.7 kb) corresponds to the previously isolated cDNA for 15-lipoxygenase, while the other (4 kb) was of unknown origin. We have isolated and characterized this 4 kb transcript. Our experiments show that it has 1.2 kb additional sequence in its 3' untranslated region, and that it is generated from genomic sequences through differential polyA site selection. We present studies to address the functional significance of the extended 3'UTR. Selection of an upstream polyadenylation signal results in production of the 2.7 kb transcript. In addition, we present here for the first time the cloning and sequence of the human 15-lipoxygenase gene, as well as the identification of regulatory elements in the promoter region of this gene.
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PMID:Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene. 922 51

There is considerable evidence to suggest that cytokines modulate the pathological cellular events that occur in human atherosclerosis. We sought to determine the effects of T-helper-lymphocyte (TH)-1- and TH2-type cytokines on the ability of human monocytes to oxidize LDL, one of the pathological processes believed to occur in atherosclerosis. The ability of opsonized zymosan (ZOP)-activated human monocytes to oxidize LDL in a 24-hour period was significantly enhanced by pretreatment of the monocytes with the TH2 cytokines, interleukin (IL)-4, or IL-13 compared with untreated monocytes. In contrast, interferon (IFN)-gamma, a TH1 cytokine, inhibited LDL oxidation by activated monocytes. Treatment with IFN-gamma also prevented the IL-4- and IL-13-mediated enhancement of LDL oxidation by ZOP-activated monocytes. Untreated or cytokine-treated unactivated monocytes did not oxidize LDL. The enhancement of LDL oxidation mediated by IL-4 or IL-13 treatment was not due to a mitogenic effect of the cytokines on the monocytes, nor to modulation of superoxide anion (O2-) production. The cytokine regulation of 15-lipoxygenase (LO) in the monocytes was also examined. IL-4 and IL-13 induction of 15-LO mRNA and 15-LO activity in the monocytes was confirmed, as was the previously reported inhibition of induction by IFN-gamma. In summary, IL-4 and IL-13 enhance the ability of activated human monocytes to oxidize LDL, whereas IFN-gamma inhibits the cell-mediated oxidation. The up- and downregulation of activated monocyte-mediated LDL oxidation by these cytokines correlates with the expression of 15-LO activity. Considerable evidence suggests that the progression of atherosclerosis includes events that are immunologically mediated, lending potential physiological relevance to these in vitro observations.
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PMID:Cytokine modulation of LDL oxidation by activated human monocytes. 935 59

15-Lipoxygenase has been suggested to play a role in atherogenesis. The proposed action of this enzyme is to oxidize low density lipoprotein (LDL) to the extent that LDL becomes a ligand for the macrophage scavenger receptor. 15-Lipoxygenase and oxidized LDL are co-localized in atherosclerotic lesions; antioxidant drugs that block the lipoxygenase also block oxidation of LDL and the progression of experimental atherosclerosis. Biochemical experiments have demonstrated that the lipoxygenase can be induced by cytokines and/or another factor(s) associated with hypercholesterolemia. However, molecular biological work has shown that induction of the enzyme alone is not sufficient to induce lesion formation. Furthermore, the mechanism of action of 15-lipoxygenase in atherogenesis remains unclear. Predictions of the stereochemistry of enzyme-oxidized linoleate products appear to conflict with the available data. In fact, most studies have discovered substantial levels of racemic 13-hydroxyoctadecadienoic acid (13-HODE) in arterial lesions rather than the stereochemically pure 13(S)-HODE expected from purified enzyme. The possibility that the generation of products of 15-lipoxygenase metabolism must occur in a specific cellular location and during a brief time window in the development of the disease has been discussed. It is also possible that the true function of the linoleate metabolites is to modulate gene expression and regulate mitogenesis, and that oxidation of LDL may play a secondary role. The advent of transgenic species that both develop atherosclerosis and either fail to express or overexpress the lipoxygenase presents an opportunity to clarify some of these issues in the near future.
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PMID:Is there a role for 15-lipoxygenase in atherogenesis? 937 14

Lipoxygenase is suggested to be involved in the early event of atherosclerosis by inducing plasma low-density lipoprotein (LDL) oxidation in the subendothelial space of the arterial wall. Since flavonoids such as quercetin are recognized as lipoxygenase inhibitors and they occur mainly in the glycoside form, we assessed the effect of quercetin and its glycosides (quercetin 3-O-beta-glucopyranoside, Q3G; quercetin 4'-O-beta-glucopyranoside, Q4'G; quercetin 7-O-beta-glucopyranoside, Q7G) on rabbit reticulocyte 15-lipoxygenase (15-LOX)-induced human LDL lipid peroxidation and compared it with the inhibition obtained by ascorbic acid and alpha-tocopherol, the main water-soluble and lipid-soluble antioxidants in blood plasma, respectively. Quercetin inhibited the formation of cholesteryl ester hydroperoxides (CE-OOH) and endogenous alpha-tocopherol consumption effectively throughout the incubation period of 6 h. Ascorbic acid exhibited an effective inhibition only in the initial stage and LDL preloaded with fivefold alpha-tocopherol did not affect the formation of CE-OOH compared with the native LDL. CE-OOH formation was inhibited by both quercetin and quercetin monoglucosides in a concentration-dependent manner. Quercetin, Q3G, and Q7G exhibited a higher inhibitory effect than Q4'G (IC50: 0.3-0.5 microM for quercetin, Q3G, and Q7G and 1.2 microM for Q4'G). While endogenous alpha-tocopherol was completely depleted after 2 h of LDL oxidation, quercetin, Q7G, and Q3G prevented the consumption of alpha-tocopherol. Quercetin and its monoglucosides were also exhausted during the LDL oxidation. These results indicate that quercetin glycosides as well as its aglycone are capable of inhibiting lipoxygenase-induced LDL oxidation more efficiently than ascorbic acid and alpha-tocopherol.
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PMID:Inhibition of mammalian 15-lipoxygenase-dependent lipid peroxidation in low-density lipoprotein by quercetin and quercetin monoglucosides. 944 20

Oxidant signalling and lipoprotein oxidation may play important roles in atherosclerotic lesion development. Given coincident localization of 15-lipoxygenase (15-LO), stereospecific products of 15-LO and epitopes of modified LDL in atherosclerotic lesions, we hypothesized that inhibition of 15-LO by PD146176, an inhibitor of 15-LO with an IC50 in cells or isolated enzyme of 0.5-0.8 microM, may limit atherosclerotic lesion development through regulation of monocyte-macrophage enrichment. Rabbits exposed to chronic endothelial denudation of the iliac-femoral artery were meal-fed a 0.25% cholesterol (C), 3% peanut oil (PNO), 3% coconut oil (CNO) diet twice daily with and without 175 mg/kg PD146176 for 12 weeks. In a second study, atherosclerotic lesions were pre-established in rabbits through chronic endothelial denudation and meal-fed a 0.5% C, 3% PNO, 3% CNO diet for 9 weeks and a 0% C/fat diet for 6 weeks prior to an 8 week administration of PD146176 at 175 mg/kg, q.d. Plasma total and lipoprotein cholesterol exposure were similar in control and PD146176-treated animals in both studies but PD146176 increased plasma triglyceride exposure 2- to 4-fold. Plasma PD146176 concentrations ranged from 99 to 214 ng/ml at 2 h post-dose. In the progression study, the iliac-femoral monocyte-macrophage area was reduced 71%, cross-sectional lesion area was unchanged and cholesteryl ester (CE) content was reduced 63%. In the regression study, size and macrophage content of iliac-femoral, fibrous plaque-like lesions were decreased 34%, CE content was reduced 19% and gross extent of thoracic aortic lesions were reduced 41%. We conclude that PD146176 can limit monocyte macrophage enrichment of atherosclerotic lesions and can attenuate development of fibrofoamy and fibrous plaque lesions in the absence of changes in plasma total or lipoprotein cholesterol concentrations.
Atherosclerosis 1998 Feb
PMID:A specific 15-lipoxygenase inhibitor limits the progression and monocyte-macrophage enrichment of hypercholesterolemia-induced atherosclerosis in the rabbit. 954 90


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