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)

We investigated the effects of mono-hydroxyeicosatetraenoic acids (HETEs) and N-formyl-methionyl-leucyl-phenylalanine (F-Met-Leu-Phe) on rat aortic smooth muscle cell migration in modified Boyden chambers. 12-HETE showed the most potent stimulatory effect on smooth muscle cell migration among the mono-HETEs tested. The optimal concentrations for cell migration were 3 X 10(-15) and 3 X 10(-13) g/ml for 12-HETE and 10(-8) g/ml for 15-HETE, 5-HETE and F-Met-Leu-Phe were inactive with these cells. As 12-HETE is biosynthesized from arachidonic acid by the 12-lipoxygenase pathway in platelets and macrophages, and 15-HETE by the 15-lipoxygenase pathway in granulocytes, the present results indicate an important role for such cells in the early phase of atherosclerosis.
Atherosclerosis 1982 Sep
PMID:Comparative effect of lipoxygenase products of arachidonic acid on rat aortic smooth muscle cell migration. 681 52

To determine the extent and origin of the stimulation of 15-lipoxygenase activity in atherosclerotic aortas, formation of hydroxy-derivatives from arachidonic acid was measured by HPLC-analysis and 15-lipoxygenase mRNA expression was investigated by RNA blot and in situ hybridization in atherosclerotic and normal rabbit aortic tissues. The synthesis of hydroxy-eicosatetraenoic acids (HETE) from exogenously added [14C]arachidonic acid was unchanged in atherosclerotic aortas in comparison with healthy aortas, but pretreatment with indomethacin demonstrated that 15-HETE production resulted essentially (75%) from cyclooxygenase activity in healthy aorta and from lipoxygenase activity in atherosclerotic aorta. The RNA blot and in situ hybridization with radiolabelled oligonucleotide probe demonstrated that 15-lipoxygenase mRNA was strictly localized in intimal thickening of atherosclerotic aortas. The immunostaining using anti-alpha smooth muscle actin, revealed that smooth muscle cell rich areas of the intimal thickening expressed 15-lipoxygenase mRNA. In addition, RNA blot hybridization indicated that cultured smooth muscle cells from atherosclerotic aortas expressed strongly 15-lipoxygenase mRNA. These results demonstrate that augmentation of 15-lipoxygenase activity in atherosclerotic aortas is correlated with 15-lipoxygenase mRNA expression in atherosclerotic plaque, and that intimal smooth muscle cells were involved, in addition to macrophages, in the expression of 15-lipoxygenase.
Atherosclerosis 1995 Mar
PMID:15-Lipoxygenase expression in smooth muscle cells from atherosclerotic rabbit aortas. 760 58

There is evidence that oxidized lipoproteins are a major contributing factor in atherosclerosis. 15-Lipoxygenase is the principal mammalian enzyme that can oxidize polysaturated fatty acids present in intact lipoproteins, and in membrane phospholipids in situ. We, and others, have reported previously that levels of the enzyme are increased in aortas of cholesterol-fed and spontaneously atherosclerotic WHHL rabbits. In the present study, rabbits were fed an atherogenic diet containing 1% cholesterol for 14 weeks, and levels of [14C]arachidonate metabolizing enzymes in the excised tissues were measured by HPLC analysis. 15-Lipoxygenase levels in heart, aortic adventitia, and lung, but not in liver, were increased up to 100-fold above controls, without major significant changes in prostaglandin endoperoxide synthases or the 5- and 12-lipoxygenases. The induced 15-lipoxygenase activity in the aortic adventitia was approximately 15 times greater than that found in the vessel wall. Hypercholesterolemia and elevated 15-lipoxygenase were associated with a 40% lowering of blood hematocrit. The hemolytic agent phenylhydrazine duplicated the effects of hypercholesterolemia on hematocrit, and induced up to 100-fold increases in 15-lipoxygenase activity in tissues within 7 days. The induced 15-lipoxygenase activities in heart and lung were 4 and 8 times greater, respectively, than in reticulocytes, previously the richest known source of the enzyme. Direct measurements of hemoglobin content also demonstrated that contaminating reticulocytes were not the source of the tissue enzyme. A similar tissue-specific activation of 15-lipoxygenase was observed in rat heart and lung, but also not in liver. It is concluded that the elevated level of 15-lipoxygenase activity previously reported in atherosclerotic aorta is symptomatic of a generalized and massive induction of the enzyme in cardio-pulmonary tissues by hypercholesterolemia, which may be related to the membrane perturbation and increased hemolysis that is induced by cholesterol feeding.
Atherosclerosis 1995 Mar
PMID:Systemic activation of 15-lipoxygenase in heart, lung, and vascular tissues by hypercholesterolemia: relationship to lipoprotein oxidation and atherogenesis. 760 64

Cellular lipoxygenases have been implicated in foam cell formation during the early stages of atherogenesis. We studied the interaction of lipoxygenases of different positional specificities with human lipoproteins and found that the arachidonate 15-lipoxygenases of rabbit and humans and the arachidonate 12-lipoxygenase of porcine leukocytes oxygenate lipoproteins as indicated by the formation of oxygenated lipids and changes in electrophoretic mobility of low density lipoprotein. The arachidonate 12-lipoxygenase of human platelets, the recombinant arachidonate 5-lipoxygenase of human leukocyte, and the soybean lipoxygenase I were less effective in oxidizing human LDL. As a major oxygenation product, esterified 13S-hydro(pero)xy-9Z,11E-octadecadienoic acid was identified for both the rabbit reticulocyte 15- and the porcine leukocyte 12-lipoxygenase. In addition, esterified 15S-hydro(pero)xy-5,8,11,13(Z,Z,Z,E)-eicosatetraenoic acid (for the rabbit 15-lipoxygenase) and 12S-hydro(pero)xy-5,8,10,14(Z,Z,E,Z)-eicosatetraenoic acid (for the porcine 12-lipoxygenase) as well as small amounts of racemic 9-hydro(pero)xy-10,12-octadecadienoic acid isomers were detected. More than 90% of the oxygenated polyenoic fatty acids were found in the ester lipid fraction, particularly in the cholesteryl esters and in various phospholipid classes (phosphatidylcholine and phosphatidylethanolamine). The possible biological significance of lipoxygenase-induced oxidative modification of lipoproteins in the pathogenesis of atherosclerosis is discussed.
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PMID:Oxidative modification of human lipoproteins by lipoxygenases of different positional specificities. 785 52

There is strong experimental evidence that oxidized low density lipoprotein (Ox-LDL) plays an important role in atherosclerosis. However, the mechanisms by which Ox-LDL is formed in vivo are unknown. To test whether 15-lipoxygenase (15-LO) could play a role in oxidation of LDL by cells, we expressed 15-LO activity in murine fibroblasts, which do not normally have 15-LO activity, and tested their ability to modify LDL. Using a retroviral vector, we prepared fibroblasts that expressed 2- to 20-fold more 15-LO activity than control fibroblasts infected with a vector containing beta-galactosidase (lacZ). Compared with LDL incubated with lacZ cells, LDL incubated with 15-LO-containing cells were enriched with lipid hydroperoxides. When these LDL samples were subsequently subjected to oxidative stress, they were more susceptible to further oxidative modification, as judged by increased conjugated diene formation and by increased ability to compete with 125I-Ox-LDL for uptake by macrophages. These findings establish that cellular 15-LO can contribute to oxidative modification of LDL, but the quantitative significance of these findings to the in vivo oxidation of LDL remains to be established.
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PMID:Enhanced levels of lipoperoxides in low density lipoprotein incubated with murine fibroblast expressing high levels of human 15-lipoxygenase. 789 Jun 29

Mounting evidence suggests that oxidative processes contribute to the pathogenesis of atherosclerosis and that antioxidants may represent a strategy to complement the lowering of lipids in the therapy of this disease. Although multiple molecular events have been identified in vitro and although it is tempting to ascribe multiple atherogenic properties to oxidized LDL, our understanding of this process remains incomplete. Further research is warranted in several areas. First, it will be important to selectively inhibit different aspects of the process to determine the relative contribution of various biological targets. In this regard pharmacological inhibition of 15-lipoxygenase in vivo in relevant animal models is required to address the question of the contribution of this enzyme to significant oxidative events. The lack of specific inhibitors has made this task more difficult. It will also be important to define the biologically active moiety of oxidized LDL to begin to determine the mechanisms through which it exerts its atherogenic effects. It is likely that alternate protein targets can be identified both downstream and upstream of the oxidative process. Research is only now beginning to elucidate the inflammatory mechanisms that account for the cellular response. Further research into adhesion events, cytokine profiles, and downstream effector molecules of the oxidative process are likely to identify alternate targets for therapeutic intervention.
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PMID:Oxidation, lipoxygenase, and atherogenesis. 801 70

Arachidonate 15-lipoxygenase (15-lipoxygenase) is a lipid-peroxidizing enzyme associated with specific inflammatory cells seen in asthma and atherosclerosis. In atherosclerosis, 15-lipoxygenase is induced in the macrophages of human and rabbit lesions and has been implicated in foam cell formation. In human lung, 15-lipoxygenase is preferentially expressed in airway epithelial cells and eosinophils. Our studies have focused both on the regulation of expression and on the structure-function relationships of the enzyme. To determine factors that could regulate expression, peripheral blood monocytes were purified and cultured with combinations of 18 factors. Only interleukin-4 (60 pM) induced 15-lipoxygenase mRNA, protein and enzymatic activity. Interferon-gamma (100 pM) inhibited the interleukin-4 dependent induction of 15-lipoxygenase. Results with cultured human airway cells were similar. These data suggest that expression of 15-lipoxygenase is regulated by interleukin-4, and that 15-lipoxygenase is a potential downstream effector molecule for this potent cytokine. In parallel studies, we have investigated determinants of positional specificity using site-directed mutagenesis and bacterial expression of human 15-lipoxygenase. Hypotheses for mutagenesis were derived from an analysis of conserved differences among multiple lipoxygenase sequences. Switching four amino acids in 15-lipoxygenase to their counterparts in 12-lipoxygenase resulted in a variant enzyme that produced equal 12- and 15-lipoxygenation. Further analysis has identified two amino acids that completely control the positional specificity of 15-lipoxygenase. These data have led to a preliminary model of the enzyme's active site region.
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PMID:Human 15-lipoxygenase: induction by interleukin-4 and insights into positional specificity. 835 18

15-lipoxygenase (15-LO) expression in artery wall cells has been demonstrated during the development of atherosclerosis in various animal models. We examined whether the expression of 15-LO in aortic endothelial cells affects the gene expression of the adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). Transient transfection of human 15-LO cDNA into bovine aortic endothelial cells led to the expression of 15-LO protein and enzymatic activity. We studied the induction of VCAM-1 mRNA in these cells. 15-LO expressing cells showed no detectable levels of VCAM-1 message. However, when TNF was added to these cells there was a synergistic increase in VCAM-1 expression relative to cells that were transfected with control plasmid pcDNA I. Our data suggest that 15-LO expression in aortic endothelium may amplify the expression of VCAM-1 induced by inflammatory stimulus during atherogenesis.
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PMID:Transient overexpression of human 15-lipoxygenase in aortic endothelial cells enhances tumor necrosis factor-induced vascular cell adhesion molecule-1 gene expression. 864 2

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

We have investigated possible mechanisms by which n-3 fatty acid-enriched macrophages enhance the oxidation of low density lipoprotein (LDL), and the ability of antioxidant vitamins to prevent this. Macrophages were enriched with n-3 fatty acids (eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid) following incubation with fish oil. These macrophages produced large amount of TBARS in medium containing metals, and showed enhanced capacity to oxidize LDL (3-4 fold increase compared to control cells) and to accumulate the modified LDL. 5,8,11,14-eicosatetraynoic acid (ETYA, 15-lipoxygenase inhibitor) and superoxide dismutase (SOD) did not inhibit the enhanced capacity of n-3 fatty acid-enriched cells to oxidize LDL. However antioxidants, (vitamin E-enriched macrophages or vitamin C in the medium), inhibited this enhanced capacity. Medium conditioned by n-3 fatty acid-enriched cells had pro-oxidant effects on metal-initiated LDL oxidation. We conclude that n-3 fatty acid-enriched macrophages display increased oxidant capacity which is not inhibited by ETYA or SOD, and that antioxidant vitamins inhibit the enhanced capacity to oxidize LDL.
Atherosclerosis 1996 Aug 02
PMID:Enhanced capacity of n-3 fatty acid-enriched macrophages to oxidize low density lipoprotein mechanisms and effects of antioxidant vitamins. 883 Sep 29


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