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

Hyperhomocysteinemia is a risk factor for atherosclerosis, and is found in the heterozygous form in approximately one-third of all individuals with coronary artery disease. The sulfhydryl group of homocysteine has been viewed as contributing to the atherogenic effects of this low-molecular-weight thiol, largely as a consequence of facilitating the generation of hydrogen peroxide from oxygen. Hydrogen peroxide, in turn, is presumed to induce dysfunction and damage to the endothelial cell, leading to attenuation of its antithrombotic and vasodilatory properties. As we have shown that endothelium-derived relaxing factor (EDRF) and other oxides of nitrogen can form adducts with thiols, we hypothesized that EDRF released from normal endothelium S-nitrosates homocysteine, rendering it nontoxic to the endothelium. We show that EDRF released from endothelial cells in the presence of homocysteine can lead to the formation of S-nitrosohomocysteine; that, like other S-nitrosothiols, S-nitrosohomocysteine induces vasorelaxation and platelet inhibition; and that, in contrast to homocysteine, S-nitrosohomocysteine does not support hydrogen peroxide generation and does not lead to endothelial dysfunction. These data suggest that normal endothelial cells modulate the adverse effects of homocysteine by facilitating the formation of the EDRF adduct, S-nitrosohomocysteine. The toxic effects of homocysteine may, then, result from an inability of the endothelium to sustain adequate production of EDRF in the face of elevated homocysteine concentration.
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PMID:Endothelium-derived relaxing factor modulates the atherothrombogenic effects of homocysteine. 128 70

Lipid peroxidation within human arterial lesions is thought to play an important role in the development of atherosclerosis. Peroxidation can be accelerated by the presence of 'catalytic' iron or copper ions. Gruel samples from advanced atherosclerotic lesions in the abdominal aortae of human cadavers were tested for pro-oxidant properties. All samples contained bleomycin-detectable iron and phenanthroline-detectable copper. Almost all gruel samples stimulated peroxidation of rat liver microsomes, and this was usually inhibited by the iron-ion chelator desferrioxamine. Some samples stimulated formation of hydroxyl radicals from H2O2 in the presence of ascorbate, a reaction again inhibited by desferrioxamine. We conclude that the interior of human advanced atherosclerotic lesions is a highly pro-oxidant environment, and that the use of copper or iron ions to promote peroxidation of low-density lipoproteins in vitro may be a valid model for events in the arterial wall.
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PMID:Stimulation of lipid peroxidation and hydroxyl-radical generation by the contents of human atherosclerotic lesions. 132 21

Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.
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PMID:Ferritin: a cytoprotective antioxidant strategem of endothelium. 151 45

A number of active oxygen species are likely implicated in the etiology or manifestation of several pathological conditions, including aging, arthritis, carcinogenesis, atherosclerosis, and muscular dystrophy. Ascorbate plays a key role in protecting cells against oxidative damage. Paradoxically, in the presence of Fe3+ or Cu2+, ascorbate can promote the generation of the same reactive oxygen species (.OH, O2-, H2O2, and ferryl ion) it is known to destroy. This prooxidant activity derives from the ability of ascorbate to reduce Fe3+ or Cu2+ to Fe2+ or Cu+, respectively, and to reduce O2 to O2-. and H2O2. Damage to nucleic acid and proteins results from the binding of either Fe2+ or Cu+ to metal binding sites on these macromolecules followed by reaction of the metal complexes with H2O2; this leads to the production of active oxygen species that attack functional groups at or near the metal binding sites.
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PMID:Ascorbic acid and oxidative inactivation of proteins. 196 58

To test antiradical medicines effect the chemical production of singlet oxygen (NaClO + H2O2) was investigated. The quantity singlet oxygen chemiluminescence was decreased in the presence of Japanese Catalin and Chine Baineiting, antirheumatic Voltaren and less strong Finish Catachrome and Carnosine. American Quinax does not possess such an effect. One of the possible starting mechanisms causing different diseases (atherosclerosis, cataract etc.) is destruction of biomembranes by active forms of oxygen.
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PMID:[Decrease of singlet oxygen chemiluminescence by the presence of carnosine]. 229 61

We have studied the ability of particulate stimuli to induce the release of reactive oxygen metabolites from sub-cultured monolayers of human endothelial cells. Basal release of superoxide (O2-) and hydrogen peroxide from undisturbed monolayers was very low (108 pmol O2- and 75 pmol H2O2 in 3 h from dishes of 3 X 10(5) cells). Addition of 1-micron diameter polystyrene microspheres, which were phagocytosed by the cells progressively, caused a dramatic increase in release of both metabolites; by 3 h, a 13.5- and 6.6-fold increase over controls was observed respectively (P less than 0.001). Addition of formaldehyde-fixed human platelets or chylomicron-size lipid particles also increased production of reactive oxygen species. Similar rises in H2O2 and O2- production were induced by treatment with 10(-7) M phorbol myristate acetate. Pretreatment of endothelial cells with neuraminidase, heparinase or heparitinase to alter their glycocalyx composition substantially enhanced the effect of microspheres on H2O2 and O2- generation. We conclude that the interactions of particles, including platelets and lipids, with endothelial cells leads to the generation of significant pericellular levels of reactive oxygen species. These metabolites can oxidise a wide variety of nearby molecules, leading to cell damage and altered uptake characteristics for lipoproteins containing peroxidized lipids. These effects are exacerbated when endothelial cell glycocalyx composition is disrupted.
Atherosclerosis 1988 Jul
PMID:Generation of reactive oxygen metabolites by phagocytosing endothelial cells. 285 Aug 6

Oxidative damage to the vascular endothelium may play an important role in the pathogenesis of atherosclerosis and aging, and may account in part for reduced vascular prostacyclin (PGI2) synthesis associated with both conditions. Using H2O2 to induce injury, we investigated the effects of oxidative damage on PGI2 synthesis in cultured endothelial cells (EC). Preincubation of EC with H2O2 produced a dose-dependent inhibition (inhibitory concentration [IC50] = 35 microM) of PGI2 formation from arachidonate. The maximum dose-related effect occurred within 1 min after exposure although appreciable H2O2 remained after 30 min (30% of original). In addition, H2O2 produced both a time- and dose-dependent injury leading to cell disruption, lactate dehydrogenase release, and 51Cr release from prelabeled cells. However, in dramatic contrast to H2O2 effects on PGI2 synthesis, loss of cellular integrity required doses in excess of 0.5 mM and incubation times in excess of 1 h. The superoxide-generating system, xanthine plus xanthine oxidase, produced a similar inhibition of PGI2 formation. Such inhibition was dependent on the generation of H2O2 but not superoxide in that catalase was completely protective whereas superoxide dismutase was not. H2O2 (50 microM) also effectively inhibited basal and ionophore A23187 (0.5 microM)-stimulated PGI2 formation. However, H2O2 had no effect on phospholipase A2 activity, because ionophore A23187-induced arachidonate release was unimpaired. To determine the effects on cyclooxygenase and PGI2 synthase, prostaglandin products from cells prelabeled with [3H]arachidonate and stimulated with ionophore A23187, or products formed from exogenous arachidonate were examined. Inhibition of cyclooxygenase but not PGI2 synthase was observed. Incubation of H2O2-treated cells with prostaglandin cyclic endoperoxide indicated no inhibition of PGI2 synthase. Thus, in EC low doses of H2O2 potently inhibit cyclooxygenase after brief exposure whereas larger doses and prolonged exposure are required for classical cytolytic effects. Surprisingly, PGI2 synthase, which is known to be extremely sensitive to a variety of lipid peroxides, is not inhibited by H2O2. Lipid solubility, enzyme location within the EC membrane, or the local availability of reducing factors may explain these results, and may be important determinants of the response of EC to oxidative stress.
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PMID:Effect of hydrogen peroxide on prostaglandin production and cellular integrity in cultured porcine aortic endothelial cells. 299 39

We have examined whether the toxic effects of homocysteine on cultured endothelial cells could result from the formation and action of hydrogen peroxide. In initial experiments with a cell-free system, micromolar amounts of copper were found to catalyze an oxygen-dependent oxidation of homocysteine. The molar ratio of homocysteine oxidized to oxygen consumed was approximately 4.0, which suggests that oxygen was reduced to water. The addition of catalase, however, decreased oxygen consumption by nearly one-half, which suggests that H2O2 was formed during the reaction. Confirming this hypothesis, H2O2 formation was detected using the horseradish peroxidase-dependent oxidation of fluorescent scopoletin. Ceruloplasmin was also found to catalyze oxidation of homocysteine and generation of H2O2 in molar amounts equivalent to copper sulfate. Finally, homocysteine oxidation was catalyzed by normal human serum in a concentration-dependent manner. Using cultured human and bovine endothelial cells, we found that homocysteine plus copper could lyse the cells in a dose-dependent manner, an effect that was completely prevented by catalase. Homocystine plus copper was not toxic to the cells. Specific injury to endothelial cells was seen only after 4 h of incubation with homocysteine plus copper. Confirming the biochemical studies, ceruloplasmin was also found to be equivalent to Cu++ in its ability to cause injury to endothelial cells in the presence of homocysteine. Since elevated levels of homocysteine have been implicated in premature development of atherosclerosis, these findings may be relevant to the mechanism of some types of chronic vascular injury.
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PMID:Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. 351 79

The effect of elastin peptides (Kappa-elastin) was investigated on human monocytes. The data presented here indicate that elastin peptides increase the intracellular Ca2+ level measured by Quin 2 fluorescence and mediate the release of beta glucuronidase and elastase. The O2 consumption and H2O2 release were stimulated in a dose-dependent manner. The early rise of cAMP was followed by a return to the original level at 30 min and by a concomitant increase of cGMP level. The action of elastin peptides on intracellular calcium level and cGMP levels may well be related to its previously demonstrated chemotactic activity. These activities may well play a role in the modifications of the extracellular matrix following elastin degradation as observed in atherosclerosis, emphysema and aging.
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PMID:Effect of elastin peptides on human monocytes: Ca2+ mobilization, stimulation of respiratory burst and enzyme secretion. 364 24

Increased generation of active oxygen species such as H2O2 and O2- may be important in vascular smooth muscle cell growth associated with atherosclerosis and restenosis. In previous work, we showed that H2O2 stimulated vascular smooth muscle cell growth and proto-oncogene expression. In the present study, we compared the effects of H2O2 and O2- on cultured rat aortic vascular smooth muscle cell growth and signal transduction. O2- was generated in a concentration-dependent manner by the naphthoquinolinedione LY83583. Vascular smooth muscle cell growth, as measured by [3H]thymidine incorporation, was stimulated by 200 mumol/L H2O2 (110% increase versus 0.1% serum) and 1 mumol/L LY83583 (175% increase) to levels comparable to 10 ng/mL platelet-derived growth factor (210% increase). Since activation of mitogen-activated protein kinase (MAP kinase) is one of the earliest growth factor signal events, the activity of MAP kinase was measured by changes in mobility on Western blot and by phosphorylation of myelin basic protein. There was a concentration-dependent increase in MAP kinase activity by LY83583 (maximum, 10 mumol/L) but not by H2O2. The time course for activation of MAP kinase by LY83583 showed a maximum at 5 to 10 minutes with return to baseline by 20 minutes. Activation of MAP kinase by LY83583 was protein kinase C dependent. Expression of MAP kinase phosphatase-1 (MKP-1), a transcriptionally regulated redox-sensitive protein tyrosine/threonine phosphatase, was also measured. Although H2O2 induced MKP-1 mRNA to a greater extent than did LY83583, the increased MKP-1 expression could not explain the inability of H2O2 to stimulate MAP kinase, because mRNA levels were not detected until 60 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential activation of mitogen-activated protein kinases by H2O2 and O2- in vascular smooth muscle cells. 754 May 16


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