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 plasma reduced glutathione (GSH) selenoperoxidase is a highly conserved enzyme. Furthermore, a small clinical study reported that patients with severe atherosclerosis had low peroxidase activities. Together these observations suggest that the peroxidase is important in preventing atherosclerosis. Yet others have reported that when the assay was run in Tris buffer, it was inactive with the concentrations of GSH found in the plasma. Second, it is known that hyperhomocysteinemia increases the rate of atherogenesis. Because there is some homology between homocysteine and the cysteine in GSH, the question is whether the hyperhomocysteinemia effect may be due to inhibition of the peroxidase. We purified the peroxidase from human plasma and determined its activity by a coupled spectrophotometric assay and a substrate disappearance chemiluminescence assay. When the peroxidase activity was determined in phosphate-buffered saline solution (PBS), there was significant activity with the reported plasma GSH concentrations (5 to 20 micromol/L). The peroxidase was exclusively in the HDL fraction. There was no correlation between the peroxidase activity and the HDL or LDL cholesterol concentrations. Finally, at physiologic concentrations of GSH (9 micromol/L), the peroxidase was inhibited by physiologic, free homocysteine concentrations (1 to 5 micromol/L). These data suggest that the peroxidase is active in vivo and may be important in protecting the endothelium from atherosclerosis by preventing oxidant injury. The homocysteine inhibition of the peroxidase suggests a possible biochemical basis for the observed association between hyperhomocysteinemia and cardiovascular disease. Our studies imply that low concentrations of this peroxidase may be an independent risk factor for atherosclerosis.
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PMID:Physiologic concentrations of homocysteine inhibit the human plasma GSH peroxidase that reduces organic hydroperoxides. 1088 28

Neutrophils and other phagocytes manufacture O(2)(-) (superoxide) by the one-electron reduction of oxygen at the expense of NADPH. Most of the O(2)(-) reacts with itself to form H(2)O(2) (hydrogen peroxide). From these agents a large number of highly reactive microbicidal oxidants are formed, including HOCl (hypochlorous acid), which is produced by the myeloperoxidase-catalyzed oxidation of Cl(-) by H(2)O(2); OH(*) (hydroxyl radical), produced by the reduction of H(2)O(2) by Fe(++) or Cu(+); ONOO(-) (peroxynitrite), formed by the reaction between O(2)(-) and NO(*); and many others. These reactive oxidants are manufactured for the purpose of killing invading microorganisms, but they also inflict damage on nearby tissues, and are thought to be of pathogenic significance in a large number of diseases. Included among these are emphysema, acute respiratory distress syndrome, atherosclerosis, reperfusion injury, malignancy and rheumatoid arthritis.
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PMID:Phagocytes and oxidative stress. 1093 76

Atherosclerosis is a chronic inflammatory process where oxidative damage within the artery wall is implicated in the pathogenesis of the disease. Mononuclear phagocytes, an inflammatory cell capable of generating a variety of oxidizing species, are early components of arterial lesions. Their normal functions include host defense and surveillance through regulated generation of diffusible radical species, reactive oxygen or nitrogen species, and HOCl (hypochlorous acid). However, under certain circumstances an excess of these oxidizing species can overwhelm local antioxidant defenses and lead to oxidant stress and oxidative tissue injury, processes implicated in the pathogenesis of atherosclerosis. This review focuses on oxidation reactions catalyzed by myeloperoxidase (MPO), an abundant heme protein secreted from activated phagocytes which is present in human atherosclerotic lesions. Over the past several years, significant evidence has accrued demonstrating that MPO is one pathway for protein and lipoprotein oxidation during the evolution of cardiovascular disease. Multiple distinct products of MPO are enriched in human atherosclerotic lesions and LDL recovered from human atheroma. However, the biological consequences of these MPO-catalyzed reactions in vivo are still unclear. Here we discuss evidence for the occurrence of MPO-catalyzed oxidation reactions in vivo and the potential role MPO plays in both normal host defenses and inflammatory diseases like atherosclerosis.
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PMID:Myeloperoxidase-generated oxidants and atherosclerosis. 1094 13

The phagocyte-derived enzyme myeloperoxidase has been recently implicated in the pathogenesis of atherosclerosis, because it catalyzes the reaction of hydrogen peroxide with chloride ions to give the highly toxic oxidant hypochlorous acid. The aim of this study was to determine the dependence of this reaction on the concentration of hydrogen peroxide and of the enzyme by means of the photometric monochlorodimedone assay. The initial rate of hypochlorous acid formation increased less than proportionally with increasing myeloperoxidase concentrations. Variation of the concentration of hydrogen peroxide had a biphasic effect, with an optimal concentration of hydrogen peroxide. Above this concentration enzyme destruction is apparently predominant. The progress curves of hypochlorous acid formation showed two distinct maxima. It was concluded that hypochlorous acid not only reacts with monochlorodimedone but also with the amino groups of myeloperoxidase to form intermediary chloramines that may further chlorinate monochlorodimedone. This was supported by the kinetics in the presence of the amino compound glycine, a competitive substrate for chlorination by hypochlorous acid. In the presence of high concentrations of glycine the progress curve rises continuously, yielding a greatly increased concentration of chlorinating species, either hypochlorous acid or chloramines. We concluded that glycine protects myeloperoxidase against hypochlorous acid-induced self-destruction.
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PMID:Kinetics of chlorination of monochlorodimedone by myeloperoxidase. 1098 30

In this study, the production of the highly toxic oxidant hypochlorous acid (HOCl) by the phagocytic enzyme myeloperoxidase (MPO) was quantitated and the concomitant alterations of low density lipoprotein (LDL) were analyzed in view of the potential role of LDL in atherosclerosis. Using the monochlorodimedone assay, it was found that HOCl is produced in micromolar concentrations. The kinetics of the decrease of tryptophan fluorescence appeared to be a sensitive method to monitor LDL alterations under near in vivo conditions. Therefore, this method was used to subsequently compare the effectiveness of MPO inhibitors that block production of HOCl with compounds that act as HOCl traps. The efficiency of MPO inhibitors to prevent LDL damage increased in the series benzohydroxamic acid < salicylhydroxamic acid < 3-amino-1,2,4-triazole < sodium azide < potassium cyanide < p-hydroxy-benzoic acid hydrazide, while for the HOCl traps the protective efficiency increased in the series glycine < taurine < methionine. We conclude that HOCl traps may have high potential therapeutic impact in vivo due to their low toxicity, although high concentrations of them would have to reach sites of inflammation. In contrast, only low concentrations of a specific MPO inhibitor would be required to irreversibly inhibit the enzyme.
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PMID:Comparison of HOCl traps with myeloperoxidase inhibitors in prevention of low density lipoprotein oxidation. 1100 81

Nitric oxide, a pivotal molecule in vascular homeostasis, is converted under aerobic conditions to nitrite. Recent studies have shown that myeloperoxidase (MPO), an abundant heme protein released by activated leukocytes, can oxidize nitrite (NO(2-)) to a radical species, most likely nitrogen dioxide. Furthermore, hypochlorous acid (HOCl), the major strong oxidant generated by MPO in the presence of physiological concentrations of chloride ions, can also react with nitrite, forming the reactive intermediate nitryl chloride. Since MPO and MPO-derived HOCl, as well as reactive nitrogen species, have been implicated in the pathogenesis of atherosclerosis through oxidative modification of low density lipoprotein (LDL), we investigated the effects of physiological concentrations of nitrite (12.5-200 microm) on MPO-mediated modification of LDL in the absence and presence of physiological chloride concentrations. Interestingly, nitrite concentrations as low as 12.5 and 25 microm significantly decreased MPO/H2O2)/Cl- -induced modification of apoB lysine residues, formation of N-chloramines, and increases in the relative electrophoretic mobility of LDL. In contrast, none of these markers of LDL atherogenic modification were affected by the MPO/H2O2/NO2-) system. Furthermore, experiments using ascorbate (12.5-200 microm) and the tyrosine analogue 4-hydroxyphenylacetic acid (12.5-200 microm), which are both substrates of MPO, indicated that nitrite inhibits MPO-mediated LDL modifications by trapping the enzyme in its inactive compound II form. These data offer a novel mechanism for a potential antiatherogenic effect of the nitric oxide congener nitrite.
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PMID:The nitric oxide congener nitrite inhibits myeloperoxidase/H2O2/ Cl- -mediated modification of low density lipoprotein. 1105 30

To study the existence of platelet activation before the onset of cerebral infarction, the ultrastructural features of platelets (7-day survival) and coagulation-fibrinolytic markers (70-100-min life span) were measured 2-12 h (acute phase), 7 days (subacute phase) and 6 months (chronic phase) after onset in 18 patients with cerebral infarction. Seven patients with atherosclerosis but without cerebral infarction and eight healthy subjects were studied as controls. Ultrastructural study included folds, pseudopods, vacuoles and centralization in addition to immunochemical staining such as platelet peroxidase and fibrinogen. Furthermore, beta-thromboglobulin, platelet factor-4, thrombin antithrombin complex and alpha(2)-plasmin inhibitor plasmin complex were examined as coagulation-fibrinolytic markers. Ultrastructural study of circulating platelets demonstrated no difference between acute and chronic phases and little difference between cerebral infarction and atherosclerosis, although plasma coagulation-fibrinolytic markers showed an increase in cerebral infarction at the acute phase but no difference among the chronic phase of cerebral infarction, atherosclerosis and normal healthy subjects. It is considered that shape change in circulating platelets was caused by pre-existed atherosclerosis rather than the thrombotic event itself though coagulation-fibrinolytic markers were derived from the thrombotic event.
Atherosclerosis 2000 Nov
PMID:Possible existence of platelet activation before the onset of cerebral infarction. 1105 16

Reactive aldehydes might have a pivotal role in the pathogenesis of atherosclerosis by covalently modifying low-density lipoprotein (LDL). However, the identities of the aldehyde adducts that form on LDL in vivo are not yet clearly established. We previously demonstrated that the haem protein myeloperoxidase oxidizes proteins in the human artery wall. We also have shown that p-hydroxyphenylacetaldehyde (pHA), the aldehyde that forms when myeloperoxidase oxidizes L-tyrosine, covalently modifies the N(epsilon)-lysine residues of proteins. The resulting Schiff base can be quantified as N(epsilon)-[2-(p-hydroxyphenyl)ethyl]lysine (pHA-lysine) after reduction with NaCNBH(3). Here we demonstrate that pHA-lysine is a marker for LDL that has been modified by myeloperoxidase, and that water-soluble, but not lipid-soluble, antioxidants inhibit the modification of LDL protein. To determine whether myeloperoxidase-generated aldehydes might modify LDL in vivo, we used a combination of isotope-dilution GC-MS to quantify pHA-lysine in aortic tissues at various stages of lesion evolution. We also analysed LDL isolated from atherosclerotic aortic tissue. Comparison of normal and atherosclerotic aortic tissue demonstrated a significant elevation (more than 10-fold) of the reduced Schiff base adduct in fatty streaks, intermediate lesions and advanced lesions compared with normal aortic tissue. Moreover, the level of pHA-lysine in LDL recovered from atherosclerotic aortic intima was 200-fold that in plasma LDL of healthy donors. These results indicate that pHA-lysine, a specific covalent modification of LDL, is generated in human atherosclerotic vascular tissue. They also raise the possibility that reactive aldehydes generated by myeloperoxidase have a role in converting LDL into an atherogenic lipoprotein.
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PMID:Elevated levels of protein-bound p-hydroxyphenylacetaldehyde, an amino-acid-derived aldehyde generated by myeloperoxidase, are present in human fatty streaks, intermediate lesions and advanced atherosclerotic lesions. 1110 75

The family of human peroxidases described includes myeloperoxidase, eosinophil peroxidase, uterine peroxidase, lactoperoxidase, salivary peroxidase, thyroid peroxidase and prostaglandin H1/2 synthases. The chemical identity of the peroxidase compound I and II oxidation states for the different peroxidases are compared. The identities of the distal and proximal amino acids of the catalytic site of each peroxidase are also compared. The gene characteristics and chromosomal location of the human peroxidase family have been tabulated and their molecular evolution discussed. Myeloperoxidase polymorphism and the mutations identified so far that affect myeloperoxidase activity and modulate their susceptibility to disease is described. The mechanisms for hypohalous and hypothiocyanate formation by the various peroxidases have been compared. The cellular function of the peroxidases and their hypohalites have been described as well as their inflammatory effects. The peroxidase catalysed cooxidation of drugs and xenobiotics that results in oxygen activation by redox cycling has been included. Low-density lipoprotein oxidation (initiation of atherosclerosis), chemical carcinogenesis, idiosyncratic drug reactions (e.g. agranulocytosis), liver necrosis or teratogenicity initiated by the cooxidation of endogenous substrates, plasma amino acids, drugs and xenobiotics catalysed by peroxidases or peroxidase containing cells have also been compared. Finally, peroxidase inhibitors currently in use for treating various diseases are described.
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PMID:Peroxidases. 1115 38

Risk factors for cardiovascular disease have been shown to exacerbate the inflammatory response and microvascular dysfunction that is normally associated with ischemia-reperfusion. The objective of this study was to determine whether hypercholesterolemia and/or hypertension alter I/R-induced expression of P-selectin in the intestinal vasculature. Male control and hypertensive (HTN) rats were placed on either a normal diet or high cholesterol diet (HCD) for at least 3 weeks resulting in hypercholesterolemia (HC). Ischemia was induced by occlusion of the superior mesenteric artery for 15 min, followed by either 30 min or 4 h of reperfusion. The dual radiolabeled antibody technique was used to quantify the rapid (30 min) and transcription-dependent (4 h) expression of P-selectin. Tissue myeloperoxidase (MPO) was used to quantify neutrophil infiltration. The constitutive (basal) expression of P-selectin did not differ among the experimental groups. Although I/R significantly increased P-selectin expression in control, HC, and HTN+HC, P-selectin expression did not increase in HTN. The HC group exhibited the largest increments in P-selectin expression and tissue MPO after I/R. The increment in P-selectin expression was not significantly attenuated in HC rats that were rendered thrombocytopenic with anti-platelet serum. Treatment with an anti-P-selectin antibody largely prevented the exaggerated MPO increase noted in HC. These findings indicate that hypercholesterolemia in contrast to hypertension enhances the expression of P-selectin in the postischemic intestinal vasculature.
Atherosclerosis 2001 Feb 01
PMID:Influence of hypercholesterolemia and hypertension on ischemia-reperfusion induced P-selectin expression. 1116 66


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