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

The roles of superoxide (O2.-), peroxynitrite, and carbon dioxide in the oxidative chemistry of nitric oxide (.NO) are reviewed. The formation of peroxynitrite from .NO and O2.- is controlled by superoxide dismutase (SOD), which can lower the concentration of superoxide ions. The concentration of CO2 in vivo is high (ca. 1 mM), and the rate constant for reaction of CO2 with -OONO is large (pH-independent k = 5.8 x 10(4) M(-l)s(-1)). Consequently, the rate of reaction of peroxynitrite with CO2 is so fast that most commonly used scavengers would need to be present at very high, near toxic levels in order to compete with peroxynitrite for CO2. Therefore, in the presence of physiological levels of bicarbonate, only a limited number of biotargets react directly with peroxynitrite. These include heme-containing proteins such as hemoglobin, peroxidases such as myeloperoxidase, seleno-proteins such as glutathione peroxidase, proteins containing zinc-thiolate centers such as the DNA-binding transcription factors, and the synthetic antioxidant ebselen. The mechanism of the reaction of CO2 with OONO produces metastable nitrating, nitrosating, and oxidizing species as intermediates. An analysis of the lifetimes of the possible intermediates and of the catalysis of peroxynitrite decompositions suggests that the reactive intermediates responsible for reactions with a variety of substrates may be the free radicals .NO2 and CO3.-. Biologically important reactions of these free radicals are, for example, the nitration of tyrosine residues. These nitrations can be pathological, but they also may play a signal transduction role, because nitration of tyrosine can modulate phosphorylation and thus control enzymatic activity. In principle, it might be possible to block the biological effects of peroxynitrite by scavenging the free radicals .NO2 and CO3.-. Because it is difficult to directly scavenge peroxynitrite because of its fast reaction with CO2, scavenging of intermediates from the peroxynitrite/CO2 reaction would provide an additional way of preventing peroxynitrite-mediated cellular effects. The biological effects of peroxynitrite also can be prevented by limiting the formation of peroxynitrite from .NO by lowering the concentration of O2.- using SOD or SOD mimics. Increased formation of peroxynitrite has been linked to Alzheimer's disease, rheumatoid arthritis, atherosclerosis, lung injury, amyotrophic lateral sclerosis, and other diseases.
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PMID:Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. 974 78

Estradiol has been documented to inhibit the oxidation of low density lipoprotein (LDL). We show that physiological concentrations of estradiol do not inhibit the oxidation of LDL by copper. LDL samples isolated from a) premenopausal and postmenopausal women and from b) women at different time periods during their menstrual cycle, who differ vastly in plasma estradiol levels, were also oxidized at the same rates by copper. In contrast, LDL samples isolated from c) women who were hyperstimulated during in vitro fertilization (IVF), with estradiol concentrations above 2000 pg/ml, were resistant to oxidation by copper. However, these LDL samples were also oxidized at a higher rate by peroxidases. More importantly, subjects with high estradiol levels also showed an increase in myeloperoxidase (MPO) protein in the plasma. Based on these results, we conclude that at physiologic concentrations, it is unlikely that estradiol could act as an antioxidant. In fact, the ability of estradiol to induce MPO and become a prooxidant might instead suggest that MPO-mediated oxidative clearance of LDL from plasma by liver might favorably influence the outcome of atherosclerosis.
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PMID:Estradiol as an antioxidant: incompatible with its physiological concentrations and function. 979 96

Oxidative modification of LDL may occur via mechanisms, which are either dependent or independent of lipid peroxidation. Peroxidation of lipids in LDL, either initiated by radicals or catalysed by myeloperoxidase, results in the generation of aldehydes which substitute lysine residues in the apolipoprotein B-100 moiety and thus in the generation of oxidised LDL. Phospholipase activity, prostaglandin synthesis and platelet adhesion/activation are associated with the release of aldehydes which induce oxidative modifications of LDL in the absence of lipid peroxidation and thus in the generation of malondialdehyde-modified LDL. Recently, we have demonstrated an association between coronary artery disease and increased plasma levels of oxidised LDL. The increase of circulating oxidised LDL is most probably due to backdiffusion of oxidised LDL from the atherosclerotic arterial wall in the blood and is independent of plaque instability. Indeed, plasma levels of oxidised LDL were very similar in patients with stable coronary artery disease and in patients with acute coronary syndromes. Acute coronary syndromes were, however, associated with increased release of malondialdehyde-modified LDL that was independent of necrosis of myocardial cells. Indeed, plasma levels of malondialdehyde-modified LDL were very similar in patients with unstable angina and patients with acute myocardial infarction, in contrast with levels of troponin I which were significantly higher in acute myocardial infarction patients. These data suggest that oxidised LDL is rather a marker of coronary atherosclerosis whereas malondialdehyde-modified LDL is rather a marker of plaque instability and atherothrombosis. At present, in the absence of prospective studies, the causative role of oxidatively modified LDL in atherothrombosis is, however, not established.
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PMID:Oxidative modification of low-density lipoproteins in atherothrombosis. 992 2

Oxidative stress and free radical-mediated cell death have been linked to diseases such as atherosclerosis, Alzheimer's disease, and cancer. Estrogens may promote, or offer protection against these conditions, by acting both as an antioxidant and prooxidant. Estrogens are converted to catecholestrogens via an oxidation step. Catecholestrogens are precursors of quinones that undergo a reversible oxidation-reduction reaction yielding semiquinones and reactive oxygen species. These semiquinones and reactive oxygen species may act as prooxidants and result in DNA and protein damage that may play a role in initiating tumor growth. Estrogen may also stimulate the peroxidase reaction, thereby promoting prooxidant reactions catalyzed by estrogen. Such reactions may be involved in enhancing the oxidizability of low-density lipoproteins (LDL). This mechanism of oxidation of LDL in plasma may actually lead to increased clearance of LDL by the liver and thereby contribute to estrogens' antiatherogenic action. On the other hand, participation of catecholestrogens in iron redox cycling may contribute to the antioxidant action of estrogens. This action might be important in sites such as the subendothelial space where estrogens are thought to inhibit LDL oxidation. Estrogens may also exert antioxidant effects by acting on genes with response elements for antioxidants. This may in turn inhibit expression of certain proteins involved in disease processes such as atherogenesis. Thus, by acting as an antioxidant and prooxidant, estrogen may produce both beneficial and adverse effects important in the prevention and pathogenesis of disease.
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PMID:Antioxidant and prooxidant actions of estrogens: potential physiological and clinical implications. 1010 11

Oxidative modification of LDL may be important in the initiation and/or progression of atherosclerosis, but the precise mechanisms through which low density lipoprotein (LDL) is oxidized are unknown. Recently, evidence for the existence of HOCl-oxidized LDL in human atherosclerotic lesions has been reported, and myeloperoxidase (MPO), which is thought to act through production of HOCl, has been identified in human atherosclerotic lesions. In the present report we describe the formation of 2,4-dinitrophenylhydrazine (DNPH)-reactive modifications in the apolipoprotein (apo) by exposure of LDL to myeloperoxidase in vitro. In contrast with the complex mixture of peptides from oxidation of LDL with reagent HOCl, oxidation with MPO in vitro produced a major tryptic peptide showing absorbance at 365 nm. This peptide was isolated and characterized as VELEVPQL(*C)SFILK..., corresponding to amino acid residues 53-66...on apoB-100. Mass spectrometric analyses of two tryptic peptides from oxidation of LDL by HOCl indicated formation of the corresponding methionine sulfoxide (M=O), cysteinyl azo (*C), RS -N= N-DNP, derivatives of EEL(*C)T(M=O)FIR and LNDLNS VLV(M=O)PTFHVPFTDLQVPS(*C)K, which suggest oxidation to the corresponding sulfinic acids (RSO2H) by HOCl. The present results demonstrate that DNPH-reactive modifications other than aldehydes and ketones can be formed in the oxidation of proteins and illustrate how characterization of specific products of protein oxidation can be useful in assessing the relative contributions of different and unexpected mechanisms to the oxidation of LDL and other target substrates. The data also suggest a direct interaction of the LDL particle with the active site on myeloperoxidase and indicate that effects of the protein microenvironment can greatly influence product formation and stability.
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PMID:Selective modification of apoB-100 in the oxidation of low density lipoproteins by myeloperoxidase in vitro. 1019 Dec 93

Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert LDL into an atherogenic form in vivo are not established. Production of reactive nitrogen species may be one important pathway, since LDL recovered from human atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive nitrogen species generated by the MPO-H2O2-NO2- system of monocytes convert LDL into a form (NO2-LDL) that is avidly taken up and degraded by macrophages, leading to massive cholesterol deposition and foam cell formation, essential steps in lesion development. Incubation of LDL with isolated MPO, an H2O2-generating system, and nitrite (NO2-)-- a major end-product of NO metabolism--resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of LDL lipid peroxidation. The time course of LDL protein nitration and lipid peroxidation paralleled the acquisition of high-affinity, concentration-dependent, and saturable binding of NO2-LDL to human monocyte-derived macrophages and mouse peritoneal macrophages. LDL modification and conversion into a high-uptake form occurred in the absence of free metal ions, required NO2-, occurred at physiological levels of Cl-, and was inhibited by heme poisons, catalase, and BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL receptor nor the scavenger receptor class A type I. Exposure of macrophages to NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and cholesteryl ester accumulation, and foam cell formation. Collectively, these results identify MPO-generated reactive nitrogen species as a physiologically plausible pathway for converting LDL into an atherogenic form.
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PMID:Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. 1035 64

The effect of oxidative modification of high-density lipoprotein (HDL) was assessed by incubation of normal HDL (obtained from Rhesus monkeys fed a stock diet) with 5 microM CuSO4 at 37 degrees C for 12 h/24 h. The physicochemical properties of oxidized-HDL (Ox-HDL) were found to be affected in terms of lipid peroxidation, as observed by the increased level of thiobarbituric acid reactive substances (nmol MDA/mg HDL protein). The biological properties of HDL were altered, since a decrease in the efflux of free cholesterol into the medium was found in the presence of Ox-HDL24h compared with normal HDL (N-HDL). The binding, uptake and degradation of 125I-LDL by macrophages increased in the presence of Ox-HDL24h. The activity of antioxidant enzymes (superoxide dismutase, catalase and glutathione-peroxidase) was reduced in monocytes in the presence of Ox-HDL. However, in the presence of N-HDL, the levels of antioxidant enzymes were maintained at a higher level than in the control (in the absence of HDL) monocytes. Furthermore, the number of monocytes adhered to aortic endothelium were found to be increased in the presence of Ox-HDL. These findings suggest that HDL is susceptible to oxidative modification. Since the parameters selected in the present study are involved in the pathogenesis of atherosclerosis, it can be postulated that the in vivo protection of HDL in atherosclerosis can be reversed in the circumstances in which HDL undergoes oxidative modification like low-density lipoprotein (LDL).
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PMID:The role of oxidized HDL in monocyte/macrophage functions in the pathogenesis of atherosclerosis in Rhesus monkeys. 1040 Jan 66

Free radicals which are produced constantly in the human body have a significant role in the development of atherosclerosis. The responsibility of leukocytes for vascular disease has been proved in several ways. Hormonally active women are protected much more against myocardial infarction than men, which fact can be explained partly by endocrinological reasons, too. The authors have set the aim to investigate whether estrogen therapy effects on the one hand the intracellular activity of the granulocyte-enzyme, myeloperoxidase (MPO), which takes place in free radical reactions and on the other hand the amount of MPO released from neutrophils. In the case of women having menopause and being treated with hormone replacement (n = 11) the intracellular activity and the amount of MPO-release increased significantly as compared to the level at the time of starting taking the medicine (p < 0.001). Based on the results it can be supposed that the vasoprotective effect of estrogens is fulfilled through their influence on the MPO enzyme, too. Besides the fact that intensified MPO activity through enhanced consumption might induce the decreased accumulation of H2O2 (a reactive oxygen species, substrate of MPO), MPO also has a role in the termination of the whole process of free radical production in granulocytes by the inactivation of the NADPH-oxidase system. This means that the growing intracellular MPO activity and the increased amount of enzyme released induce the decrease of the amount of free radicals produced during the "respiratory burst" and this is advantageous from the point of view of vasoprotection. The increased MPO activity and the NADPH-oxidase inactivation supposed to be elicited by it, might have further positive consequences since MPO has an effect on HDL-metabolism and the outflow of cholesterol from "foam cells", NADPH-oxidase has a suspected role in LDL-oxidation and NADPH is one of the cofactors of NO-synthase (NOS). The decreased superoxide anion level on the other hand may mitigate the chance of the neutralizing of nitric oxide (NO) by it. The superoxide anion is a potent vasoconstrictor and therefore, its diminished production may be beneficial, i.e. decreases the risk of coronary spasm. The new conceptual synthesis worked out by the authors may provide a possible explanation of the increased susceptibility to infections during steroid treatment, too.
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PMID:[Changes in the myeloperoxidase activity of human neutrophilic granulocytes and the amount of enzyme deriving from them under the effect of estrogen]. 1044 40

Flavonoids containing phenol B rings, e.g. naringenin, naringin, hesperetin and apigenin, formed prooxidant metabolites that oxidised NADH upon oxidation by peroxidase/H2O2. Extensive oxygen uptake occurred which was proportional to the NADH oxidised and was increased up to twofold by superoxide dismutase. Only catalytic amounts of flavonoids and H2O2 were required indicating a redox cycling mechanism that activates oxygen and generates H2O2. NADH also prevented the oxidative destruction of flavonoids by peroxidase/H2O2 until the NADH was depleted. These results suggest that prooxidant phenoxyl radicals formed by these flavonoids cooxidise NADH to form NAD radicals which then activated oxygen. Similar oxygen activation mechanisms by other phenoxyl radicals have been implicated in the initiation of atherosclerosis and carcinogenesis by xenobiotic phenolic metabolites. This is the first time that a group of flavonoids have been identified as prooxidants independent of transition metal catalysed autoxidation reactions.
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PMID:Oxygen activation during peroxidase catalysed metabolism of flavones or flavanones. 1047 12

Low density lipoproteins (LDL) can bind to glycosaminoglycans and proteoglycans rich in heparin and chondroitin sulphate in the arterial intima and may become a target for atherogenic modification by myeloperoxidase activity. We have examined the susceptibility of resolubilized LDL, that has been precipitated from serum with heparin (HepLDL), to peroxidase-H2O2-catalysed oxidation and the effects of antioxidants and components of human serum on the oxidation. HepLDL was oxidised rapidly by horse radish peroxidase (HRP) and H2O2 (mean t1/2max for conjugated diene formation, 3 min) while there was little oxidation of native LDL or native LDL precipitated with polyethyleneglycol and resolubilised during the 30 min incubation period. The formation of thiobarbituric acid reacting substances (TBARS) essentially paralleled that of conjugated dienes during oxidation of HepLDL. HepLDL was also more rapidly oxidised than native LDL by myeloperoxidase-H2O2. Oxidation of HepLDL by peroxidases did not require free tyrosine, was almost totally inhibited by butylated hydroxytoluene (BHT) and ascorbate, and was unaffected by vitamin E and urate. Increasing concentrations (0-14.9%) of beta-lipoprotein deficient serum (BLPDS) significantly (P<0.0001) inhibited the formation of TBARS during HepLDL oxidation catalysed by HRP and partially inhibited the corresponding myeloperoxidase-catalysed oxidation. This inhibitory activity was removed by dialysis and gel-filtration of BLPDS and was not restored by addition of magnesium ions used in the isolation of BLPDS, or physiological levels of ascorbate, tyrosine and reduced thiols (cysteine) to gel-filtered BLPDS. The results indicate that LDL from complexes with glycosaminoglycans are highly susceptible to oxidation by peroxidases, particularly at low levels of water soluble antioxidants, and that vulnerability of these LDL to myeloperoxidase oxidation remains in the presence of serum components that should exist in the arterial intima. These findings may be relevant to the oxidative modification of LDL that becomes trapped by binding to arterial proteoglycans and to the formation of myeloperoxidase-modified LDL in the artery wall.
Atherosclerosis 1999 Oct
PMID:Oxidation of heparin-treated low density lipoprotein by peroxidases. 1053 77


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