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

Oxidation of low density lipoprotein (LDL) has been shown to occur in the artery wall of atherosclerotic lesions in both animal models and human arteries. The oxidant(s) responsible for initiating this process are under intensive investigation and 15-lipoxygenase has been suggested in this context. Another possibility is that nitric oxide and superoxide, generated by cells present in the artery wall, react together to form peroxynitrite which decomposes to form the highly reactive hydroxyl radical. In the present study we have modelled the simultaneous generation of superoxide and nitric oxide by using the sydnonimine, SIN-1 and have investigated its effects on LDL. SIN-1 liberates both superoxide and nitric oxide during autooxidation resulting in the formation of hydroxyl radicals. We have demonstrated that superoxide generated by SIN-1 is not available to take part in a dismutation reaction since it reacts preferentially with nitric oxide. It follows, therefore, that during the autooxidation of SIN-1 little or no superoxide, or perhydroxyl radical will be available to initiate lipid peroxidation. We have shown that SIN-1 is capable of initiating the peroxidation of LDL and also converts the lipoprotein to a more negatively charged form. The SIN-1-dependent peroxidation of LDL is completely inhibited by superoxide dismutase which scavenges superoxide. Neither sodium nitroprusside or S-nitroso-N-acetyl penicillamine, which only produce nitric oxide, are able to modify LDL. These results are consistent with the hypothesis that a product of superoxide and nitric oxide could oxidize lipoproteins in the artery wall and so contribute to the pathogenesis of atherosclerosis in vivo.
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PMID:The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. 133 19

Oxidative modification of low density lipoproteins and tissue lipids has been proposed to be involved in the pathogenesis of atherosclerosis. We examined human atherosclerotic lesions of various stages from fifteen victims of acute heart failure and detected substantial amounts of oxygenated fatty acids in the tissue ester lipids. The degree of lipid oxygenation correlated with the stage of advancement of the lesion. More than 85% of the oxygenated fatty acids were localized in the cholesterol esters, whereas phospholipids contained only small amounts. Structure elucidation of the oxygenation products indicated a nonspecific product pattern of various isomers of keto- and hydroxy-octadecadienoic acid. The data presented suggest an involvement of lipid peroxidation in the pathogenesis of atherosclerosis and indicate that the majority of the oxygenation products are formed via nonspecific, non-enzymatic reactions possibly initiated by the action of a 15-lipoxygenase.
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PMID:Structure elucidation of oxygenated lipids in human atherosclerotic lesions. 141 75

Oxidized low density lipoprotein (LDL) may play an important role in the pathogenesis of atherosclerosis. Recent evidence strongly suggests that oxidized LDL is present in atherosclerotic lesions in vivo: 1) LDL isolated from human and rabbit lesions (but not from normal intima) resembles oxidized LDL in its physical, chemical and immunological properties; 2) Oxidized LDL and/or oxidation specific lipid-protein adducts can be demonstrated in human and rabbit lesions by immunocytochemical techniques; 3) Human and rabbit serum contains autoantibodies against oxidized LDL and oxidation specific lipid-protein adducts; 4) atherosclerotic lesions contain IgG that recognizes oxidized LDL and 5) antioxidant therapy slows the development of atherosclerotic lesions in rabbits. Atherosclerosis in human and rabbit arteries may be linked to macrophage-induced oxidative modification of LDL mediated by 15-lipoxygenase which leads to an enhanced uptake of LDL in macrophages by way of the scavenger receptor(s). The identification of LDL oxidation as one of the key events in the early pathogenesis of atherosclerosis offers an interesting possibility to reduce atherosclerosis by antioxidants, enzyme inhibitors and other compounds that protect LDL against oxidative damage and/or reduce the subsequent harmful effects of oxidized LDL on various cellular functions.
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PMID:Macrophages and oxidized low density lipoproteins in the pathogenesis of atherosclerosis. 172 25

The oxidative modification of low density lipoprotein (LDL) may play an important role in the pathogenesis of atherosclerosis. LDL can be oxidatively modified in vitro by endothelial cells, mouse peritoneal macrophages, or copper ions. Studies using lipoxygenase inhibitors have suggested that lipoxygenase(s) is required for the cellular modification of LDL [Rankin, S. M., Parthasarathy, S. & Steinberg, D. (1991) J. Lipid Res. 32, 449-456]. We have reexamined the effect of lipoxygenase inhibitors on cellular modification and found that (i) inhibitors specific for 5-lipoxygenase do not block LDL modification; (ii) inhibitors that block lipoxygenase by donating one electron to the enzyme (reductive inactivation) prevent LDL modification by cells and also modification mediated by copper ions, implying that they act as general antioxidants; (iii) the lipoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid blocks 15-lipoxygenase activity in intact macrophages at concentrations 100 times less than those required to block LDL modification by macrophages; and (iv) 5,8,11,14-eicosatetraynoic acid is cytotoxic at concentrations about twice those required to prevent modification. Furthermore, macrophages and the RECB4 line of endothelial cells modify LDL with similar efficiencies despite dramatic differences in 15-lipoxygenase activity. Thus we conclude that neither 5-lipoxygenase nor 15-lipoxygenase is required for modification of LDL by cultured cells.
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PMID:Cellular oxidative modification of low density lipoprotein does not require lipoxygenases. 172 78

Arachidonate 15-lipoxygenase (arachidonate:oxygen 15-oxidoreductase, EC 1.13.11.33) is a lipid-peroxidating enzyme that is implicated in oxidizing low density lipoprotein to its atherogenic form. Monocyte/macrophage 15-lipoxygenase is present in human atherosclerotic lesions. To pursue a basis for induction of the enzyme, which is not present in blood monocytes, the ability of relevant cytokines to regulate its expression was investigated. Interleukin 4 (IL-4), among 16 factors tested, specifically induced 15-lipoxygenase mRNA and protein in cultured human monocytes. Interferon gamma and hydrocortisone inhibited this induction. High-performance liquid chromatography analysis of lipid extracts from IL-4-treated monocytes detected 15-lipoxygenase products esterified to the cellular membrane lipids, indicating enzymatic action on endogenous substrates. Stimulation of IL-4-treated monocytes with calcium ionophore or opsonized zymosan A enhanced the formation of 15-lipoxygenase products. These data identify IL-4 and interferon gamma as physiological regulators of lipoxygenase expression and suggest an important link between 15-lipoxygenase function and the immune/inflammatory response in atherosclerosis as well as other diseases.
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PMID:Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. 172 92

Arachidonate 15-lipoxygenase (an n-6 lipoxygenase) has been purified to homogeneity, cloned and expressed and appears to be a highly regulated enzyme showing pronounced tissue specificity. The enzyme is expressed prominently in the reticulocyte where it appears to be under posttranscriptional control and may play a key physiological role in reticulocyte maturation by initiating mitochondrial breakdown. 15-Lipoxygenase is also expressed in significant quantities in airway epithelial cells and eosinophils although no clear role for this enzyme in these cell types has been defined. The enzyme catalyzes the conversion of free arachidonic acid to 15-HPETE, free linoleic acid to 13-HPOD and can also oxygenate polyenoic acids esterified in phospholipids. A number of potential physiological and pathological roles for products of this enzyme have been postulated. These include a physiological role in prolactin secretion from pituitary cells and in the initiation of the acrosome reaction in spermatozoa. An important pathological role in the oxidation of LDL by macrophages has also been proposed, indicating that the enzyme could be a pharmacological target for the treatment of atherosclerosis.
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PMID:Arachidonate 15-lipoxygenase; characteristics and potential biological significance. 191 Aug 64

The three mammalian lipoxygenases are named according to the carbon position (5, 12 or 15) at which they catalyse the oxygenation of arachidonic acid; they are implicated in inflammatory disorders, for example 15-lipoxygenase is induced in atherosclerosis and can oxidize low-density lipoprotein to its atherogenic form. To identify what determines this positional specificity, we have exchanged conserved differences in the isoforms of 12- and 15-lipoxygenases. Substitution of methionine with valine at position 418 of human 15-lipoxygenase results in an enzyme that performs 12- and 15-lipoxygenation equally. This effect can be mimicked by incubating wild-type 15-lipoxygenase with a synthetically altered substrate which has its doubly allylic methylene carbons shifted by one carbon relative to arachidonic acid. Other mutations at the neighbouring amino acids 416 and 417 give an enzyme which performs 12- and 15-lipoxygenation in a ratio of 15:1. These results indicate that this region might position the substrate in the active site.
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PMID:A primary determinant for lipoxygenase positional specificity. 194 93

Aortas from atherosclerotic rabbits have increased levels of 15-lipoxygenase, but the relationship between induction of this enzyme and the atherosclerotic process has not been defined. We found that dietary administration of cortisone acetate significantly suppressed atherosclerotic plaque formation in both Watanabe Heritable Hyperlipidemic (WHHL) and cholesterol-fed WHHL/NZW heterozygous rabbits. There was, however, no corresponding decrease in the elevated 15-lipoxygenase activity. In addition, the elevated 15-lipoxygenase activity in atherosclerotic rabbit aortas was uniformly distributed throughout the aorta, and was not preferentially localized in the lesions. These results indicate that induction of the 15-lipoxygenase is not necessarily causally related to plaque development, and that plaques are not the major source of the increased enzyme activity. However, the results confirm that hypercholesterolemia is a necessary condition for both atherosclerosis and 15-lipoxygenase induction, suggesting that perhaps the 15-lipoxygenase may represent a protective response to the hyperlipidemic stress. This possibility is supported by the finding that the induced 15-lipoxygenase converts linoleic acid, which is the predominant essential fatty acid in aorta, to 13-hydroxyoctadecadienoic acid (13-HODE). This compound is a chemorepellant factor for platelets, inhibits platelet thromboxane synthesis, and stimulates prostacyclin synthesis by endothelial cells.
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PMID:Relationship of vascular 15-lipoxygenase induction to atherosclerotic plaque formation in rabbits. 207 42

Mammalian tissues contain 5-, 12- and 15-lipoxygenases. Only the 15-lipoxygenase can act on linoleic acid, the predominant essential fatty acid of tissues and plasma, producing 13-hydroxyoctadecadienoic acid (13-HODE). Intracellular production of 13-HODE renders endothelial cells resistant to platelet adhesion, while its hydroperoxy precursor, 13-HPODE, synergises with the platelet anti-aggregatory factor prostacyclin. We have found that a 15-lipoxygenase activity is induced in aortas of cholesterol-fed and Watanabe Heritable Hyperlipidemic (WHHL) rabbits. Aortic tissue from WHHL rabbits incubated with 3H-linoleic acid produced a major metabolite identified as 13-HODE, which was formed with an efficiency comparable to the synthesis 15-HETE from arachidonic acid. These findings indicate that the increased aortic 15-lipoxygenase in vascular tissue is capable of producing 13-HODE in vivo. Since platelet adhesion is increased in atherogenesis, and thrombogenesis is a major complication of advanced atherosclerosis, it is suggested that induction of this enzyme may be a protective response to hypercholesterolemia.
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PMID:The induced lipoxygenase in atherosclerotic aorta converts linoleic acid to the platelet chemorepellant factor 13-HODE. 250 64

The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for familial hypercholesterolemia, has a deficiency in low density lipoprotein (LDL) receptor binding and exhibits elevated plasma lipoprotein levels and spontaneous atherosclerosis. Since atherosclerotic plaque formation has a number of features in common with the inflammatory process, we have investigated the effect of dietary supplementation with an anti-inflammatory steroid (cortisone acetate, 5 mg daily for 3 months) on atherosclerosis using the WHHL rabbit as a model. Atherosclerotic plaque formation in cortisone-fed animals was reduced by about 60% compared to control WHHL rabbits. Steroid administration increased circulating cholesterol levels modestly and triglycerides were increased about 6-fold. While very low density lipoprotein (VLDL)-cholesterol was increased, LDL-cholesterol levels were decreased and the particle was more triglyceride-enriched as well as less dense. Steroid-fed animals also exhibited decreased platelet aggregation and increased aortic 15-lipoxygenase activity. The histological observations showed typical fibrous plaques in aortas of both control and cortisone-fed rabbits, with intima thickened by foamy macrophages and subcellular lipoproteinaceous debris covered by a fibrous cap. These findings thus indicate that steroids reduce the rate of plaque initiation or progression but do not significantly change the histological appearance of the lesion.
Atherosclerosis 1989 Apr
PMID:Anti-inflammatory drugs in experimental atherosclerosis. 7. Spontaneous atherosclerosis in WHHL rabbits and inhibition by cortisone acetate. 254 22


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