The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform
Jay W Heinecke - One of the best experts on this subject based on the ideXlab platform.
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neuronal expression of Myeloperoxidase is increased in alzheimer s disease
Journal of Neurochemistry, 2004Co-Authors: Pattie S Green, Armando J Mendez, Jason S Jacob, Jan R Crowley, Whit Growdon, Bradley T Hyman, Jay W HeineckeAbstract:Myeloperoxidase, a heme protein expressed by professional phagocytic cells, generates an array of oxidants which are proposed to contribute to tissue damage during inflammation. We now report that enzymatically active Myeloperoxidase and its characteristic amino acid oxidation products are present in human brain. Further, expression of Myeloperoxidase is increased in brain tissue showing Alzheimer's neuropathology. Consistent with expression in phagocytic cells, Myeloperoxidase immunoreactivity was present in some activated microglia in Alzheimer brains. However, the majority of immunoreactive material in brain localized with amyloid plaques and, surprisingly, neurons including granule and pyramidal neurons of the hippocampus. Confirming neuronal localization of the enzyme, several neuronal cell lines as well as primary neuronal cultures expressed Myeloperoxidase protein. Myeloperoxidase mRNA was also detected in neuronal cell lines. These results reveal the unexpected presence of Myeloperoxidase in neurons. The increase in neuronal Myeloperoxidase expression we observed in Alzheimer disease brains raises the possibility that the enzyme contributes to the oxidative stress implicated in the pathogenesis of the neurodegenerative disorder.
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Myeloperoxidase produces nitrating oxidants in vivo.
Journal of Clinical Investigation, 2002Co-Authors: Joseph P Gaut, Jaeman Byun, Abderrazzaq Belaaouaj, Richard S Hotchkiss, Hung D. Tran, Wendy M. Lauber, James A. Carroll, Jay W HeineckeAbstract:Despite intense interest in pathways that generate reactive nitrogen species, the physiologically relevant mechanisms for inflammatory tissue injury remain poorly understood. One possible mediator is Myeloperoxidase, a major constituent of neutrophils, monocytes, and some populations of macrophages. The enzyme uses hydrogen peroxide and nitrite to generate 3-nitrotyrosine in vitro. To determine whether Myeloperoxidase produces nitrating intermediates in vivo, we used isotope dilution gas chromatography/mass spectrometry to quantify 3-nitrotyrosine in two models of peritoneal inflammation: mice infected with Klebsiella pneumoniae and mice subjected to cecal ligation and puncture. Both models developed an intense neutrophil inflammatory response, and the inflammatory fluid contained markedly elevated levels of 3-chlorotyrosine, a marker of Myeloperoxidase action. In striking contrast, 3-nitrotyrosine levels rose only in the mice infected with K. pneumoniae. Levels of total nitrite and nitrate were 20-fold higher in mice injected with K. pneumoniae than in mice subjected to cecal ligation and puncture. Levels of 3-nitrotyrosine failed to increase in mice infected with K. pneumoniae that lacked functional Myeloperoxidase. Our observations provide strong evidence that Myeloperoxidase generates reactive nitrogen species in vivo and that it operates in this fashion only when nitrite and nitrate become available.
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neutrophils employ the Myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Joseph P Gaut, Hung Duy Tran, Jaeman Byun, Jeffrey P Henderson, Grace M Richter, Marie Luise Brennan, Aldons J Lusis, Abderrazzaq Belaaouaj, Richard S Hotchkiss, Jay W HeineckeAbstract:The Myeloperoxidase system of neutrophils uses hydrogen peroxide and chloride to generate hypochlorous acid, a potent bactericidal oxidant in vitro. In a mouse model of polymicrobial sepsis, we observed that mice deficient in Myeloperoxidase were more likely than wild-type mice to die from infection. Mass spectrometric analysis of peritoneal inflammatory fluid from septic wild-type mice detected elevated concentrations of 3-chlorotyrosine, a characteristic end product of the Myeloperoxidase system. Levels of 3-chlorotyrosine did not rise in the septic Myeloperoxidase-deficient mice. Thus, Myeloperoxidase seems to protect against sepsis in vivo by producing halogenating species. Surprisingly, levels of 3-bromotyrosine also were elevated in peritoneal fluid from septic wild-type mice and were markedly reduced in peritoneal fluid from septic Myeloperoxidase-deficient mice. Furthermore, physiologic concentrations of bromide modulated the bactericidal effects of Myeloperoxidase in vitro. It seems, therefore, that Myeloperoxidase can use bromide as well as chloride to produce oxidants in vivo, even though the extracellular concentration of bromide is at least 1,000-fold lower than that of chloride. Thus, Myeloperoxidase plays an important role in host defense against bacterial pathogens, and bromide might be a previously unsuspected component of this system.
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macrophage Myeloperoxidase regulation by granulocyte macrophage colony stimulating factor in human atherosclerosis and implications in acute coronary syndromes
American Journal of Pathology, 2001Co-Authors: Seigo Sugiyama, Jay W Heinecke, Yoshikatsu Okada, Galina K Sukhova, Renu Virmani, Peter LibbyAbstract:Inflammation and oxidative stress contribute to the pathogenesis of many human diseases including atherosclerosis. Advanced human atheroma contains high levels of the enzyme Myeloperoxidase that produces the pro-oxidant species, hypochlorous acid (HOCl). This study documents increased numbers of Myeloperoxidase-expressing macrophages in eroded or ruptured plaques causing acute coronary syndromes. In contrast, macrophages in human fatty streaks contain little or no Myeloperoxidase. Granulocyte macrophage colony-stimulating factor, but not macrophage colony-stimulating factor, selectively regulates the ability of macrophages to express Myeloperoxidase and produce HOCl in vitro. Moreover, Myeloperoxidase-positive macrophages in plaques co-localized with granulocyte macrophage colony-stimulating factor. Pro-inflammatory stimuli known to be present in human atherosclerotic plaque, including CD40 ligand, lysophosphatidylcholine, or cholesterol crystals, could induce release of Myeloperoxidase from HOCl production by macrophages in vitro. HOCl-modified proteins accumulated at ruptured or eroded sites of human coronary atheroma. These results identify granulocyte macrophage colony-stimulating factor as an endogenous regulator of macrophage Myeloperoxidase expression in human atherosclerosis and support a particular role for the Myeloperoxidase-expressing macrophages in atheroma complication and the acute coronary syndromes.
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Immunohistochemical detection of Myeloperoxidase and its oxidation products in Kupffer cells of human liver
American Journal of Pathology, 2001Co-Authors: Kyle E. Brown, Elizabeth M Brunt, Jay W HeineckeAbstract:Oxidative damage to tissue proteins has been implicated in the pathogenesis of liver disease, but the mechanisms that promote oxidation in vivo are unclear. Hydrogen peroxide is transformed into an array of potentially damaging reactants by the heme protein Myeloperoxidase. This proinflammatory enzyme is expressed by circulating neutrophils and monocytes but is generally thought to be absent from tissue macrophages. To determine whether Myeloperoxidase is present in Kupffer cells, the fixed-tissue macrophages of liver, Western blot analysis, and immunohistochemistry were performed. Two different antibodies monospecific for Myeloperoxidase identified a 60-kd protein, the predicted molecular mass of Myeloperoxidase, in human liver extracts. Immunostaining detected the enzyme in sinusoidal lining cells of normal and diseased human livers. Immunofluorescence confocal microscopy demonstrated co-localization of Myeloperoxidase and CD68, a monocyte/macrophage marker, in sinusoidal lining cells. Numerous Myeloperoxidase-expressing cells were also evident in the fibrous septa of cirrhotic livers. Immunostaining with an antibody to proteins modified by hypochlorous acid, a characteristic product of the enzyme, indicated that Myeloperoxidase is enzymatically active in cases of acute liver injury and cirrhosis. These findings identify Myeloperoxidase as a component of human Kupffer cells. Oxidative damage resulting from the action of Myeloperoxidase may contribute to acute liver injury and hepatic fibrogenesis. © 2001 Elsevier Science Ltd. All rights reserved.
Anthony J Kettle - One of the best experts on this subject based on the ideXlab platform.
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ceruloplasmin is an endogenous inhibitor of Myeloperoxidase
Journal of Biological Chemistry, 2013Co-Authors: Anna L P Chapman, Christine C Winterbourn, Tessa J Mocatta, Sruti Shiva, Antonia Seidel, Brian Chen, Irada Khalilova, Martina Paumannpage, Guy N L Jameson, Anthony J KettleAbstract:Abstract Myeloperoxidase is a neutrophil enzyme that promotes oxidative stress in numerous inflammatory pathologies. It uses hydrogen peroxide to catalyze the production of strong oxidants including chlorine bleach and free radicals. A physiological defense against the inappropriate action of this enzyme has yet to be identified. We found that Myeloperoxidase oxidized 75% of the ascorbate in plasma from ceruloplasmin knock-out mice, but there was no significant loss in plasma from wild type animals. When Myeloperoxidase was added to human plasma it became bound to other proteins and was reversibly inhibited. Ceruloplasmin was the predominant protein associated with Myeloperoxidase. When the purified proteins were mixed, they became strongly but reversibly associated. Ceruloplasmin was a potent inhibitor of purified Myeloperoxidase, inhibiting production of hypochlorous acid by 50% at 25 nm. Ceruloplasmin rapidly reduced Compound I, the FeV redox intermediate of Myeloperoxidase, to Compound II, which has FeIV in its heme prosthetic groups. It also prevented the fast reduction of Compound II by tyrosine. In the presence of chloride and hydrogen peroxide, ceruloplasmin converted Myeloperoxidase to Compound II and slowed its conversion back to the ferric enzyme. Collectively, our results indicate that ceruloplasmin inhibits Myeloperoxidase by reducing Compound I and then trapping the enzyme as inactive Compound II. We propose that ceruloplasmin should provide a protective shield against inadvertent oxidant production by Myeloperoxidase during inflammation.
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Reactions of superoxide with Myeloperoxidase.
Biochemistry, 2007Co-Authors: Anthony J Kettle, Robert F Anderson, Mark B. Hampton, Christine C WinterbournAbstract:When neutrophils ingest bacteria, they discharge superoxide and Myeloperoxidase into phagosomes. Both are essential for killing of the phagocytosed micro-organisms. It is generally accepted that superoxide is a precursor of hydrogen peroxide which Myeloperoxidase uses to oxidize chloride to hypochlorous acid. Previously, we demonstrated that superoxide modulates the chlorination activity of Myeloperoxidase by reacting with its ferric and compound II redox states. In this investigation we used pulse radiolysis to determine kinetic parameters of superoxide reacting with redox forms of Myeloperoxidase and used these data in a steady-state kinetic analysis. We provide evidence that superoxide reacts with compound I and compound III. Our estimates of the rate constants for the reaction of superoxide with compound I, compound II, and compound III are 5 × 106 M-1 s-1, 5.5 ± 0.4 × 106 M-1 s-1, and 1.3 ± 0.2 × 105 M-1 s-1, respectively. These reactions define new activities for Myeloperoxidase. It will act as a su...
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modeling the reactions of superoxide and Myeloperoxidase in the neutrophil phagosome implications for microbial killing
Journal of Biological Chemistry, 2006Co-Authors: Christine C Winterbourn, Mark B. Hampton, John H Livesey, Anthony J KettleAbstract:Abstract Neutrophils kill bacteria by ingesting them into phagosomes where superoxide and cytoplasmic granule constituents, including Myeloperoxidase, are released. Myeloperoxidase converts chloride and hydrogen peroxide to hypochlorous acid (HOCl), which is strongly microbicidal. However, the role of oxidants in killing and the species responsible are poorly understood and the subject of current debate. To assess what oxidative mechanisms are likely to operate in the narrow confines of the phagosome, we have used a kinetic model to examine the fate of superoxide and its interactions with Myeloperoxidase. Known rate constants for reactions of Myeloperoxidase have been used and substrate concentrations estimated from neutrophil morphology. In the model, superoxide is generated at several mm/s. Most react with Myeloperoxidase, which is present at millimolar concentrations, and rapidly convert the enzyme to compound III. Compound III turnover by superoxide is essential to maintain enzyme activity. Superoxide stabilizes at ∼25 μm and hydrogen peroxide in the low micromolar range. HOCl production is efficient if there is adequate chloride supply, but further knowledge on chloride concentrations and transport mechanisms is needed to assess whether this is the case. Low Myeloperoxidase concentrations also limit HOCl production by allowing more hydrogen peroxide to escape from the phagosome. In the absence of Myeloperoxidase, superoxide increases to >100 μm but hydrogen peroxide to only ∼30 μm. Most of the HOCl reacts with released granule proteins before reaching the bacterium, and chloramine products may be effectors of its antimicrobial activity. Hydroxyl radicals should form only after all susceptible protein targets are consumed.
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Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase *
Journal of Biological Chemistry, 2005Co-Authors: Valdecir Farias Ximenes, Anthony J Kettle, Sueli De Oliveira Silva, Maria Regina Da Cunha Rodrigues, Luiz Henrique Catalani, Ghassan J. Maghzal, Ana CampaAbstract:Abstract Myeloperoxidase uses hydrogen peroxide to oxidize numerous substrates to hypohalous acids or reactive free radicals. Here we show that neutrophils oxidize melatonin to N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) in a reaction that is catalyzed by Myeloperoxidase. Production of AFMK was highly dependent on superoxide but not hydrogen peroxide. It did not require hypochlorous acid, singlet oxygen, or hydroxyl radical. Purified Myeloperoxidase and a superoxide-generating system oxidized melatonin to AFMK and a dimer. The dimer would result from coupling of melatonin radicals. Oxidation of melatonin was partially inhibited by catalase or superoxide dismutase. Formation of AFMK was almost completely eliminated by superoxide dismutase but weakly inhibited by catalase. In contrast, production of melatonin dimer was enhanced by superoxide dismutase and blocked by catalase. We propose that Myeloperoxidase uses superoxide to oxidize melatonin by two distinct pathways. One pathway involves the classical peroxidation mechanism in which hydrogen peroxide is used to oxidize melatonin to radicals. Superoxide adds to these radicals to form an unstable peroxide that decays to AFMK. In the other pathway, Myeloperoxidase uses superoxide to insert dioxygen into melatonin to form AFMK. This novel activity expands the types of oxidative reactions Myeloperoxidase can catalyze. It should be relevant to the way neutrophils use superoxide to kill bacteria and how they metabolize xenobiotics.
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Biomarkers of Myeloperoxidase-derived hypochlorous acid.
Free Radical Biology and Medicine, 2000Co-Authors: Christine C Winterbourn, Anthony J KettleAbstract:Abstract Hypochlorous acid is the major strong oxidant generated by neutrophils. The heme enzyme Myeloperoxidase catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride. Although Myeloperoxidase has been implicated in the tissue damage that occurs in numerous diseases that involve inflammatory cells, it has proven difficult to categorically demonstrate that it plays a crucial role in any pathology. This situation should soon be rectified with the advent of sensitive biomarkers for hypochlorous acid. In this review, we outline the advantages and limitations of chlorinated tyrosines, chlorohydrins, 5-chlorocytosine, protein carbonyls, antibodies that recognize HOCl-treated proteins, and glutathione sulfonamide as potential biomarkers of hypochlorous acid. Levels of 3-chlorotyrosine and 3,5-dichlorotyrosine are increased in proteins after exposure to low concentrations of hypochlorous acid and we conclude that their analysis by gas chromatography and mass spectrometry is currently the best method available for probing the involvement of oxidation by Myeloperoxidase in the pathology of particular diseases. The appropriate use of other biomarkers should provide complementary information. Keywords—Free radicals, Myeloperoxidase, Neutrophil oxidant, Hypochlorous acid, Chlorotyrosine, Chlorohydrin, Oxidant biomarker
Christine C Winterbourn - One of the best experts on this subject based on the ideXlab platform.
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ceruloplasmin is an endogenous inhibitor of Myeloperoxidase
Journal of Biological Chemistry, 2013Co-Authors: Anna L P Chapman, Christine C Winterbourn, Tessa J Mocatta, Sruti Shiva, Antonia Seidel, Brian Chen, Irada Khalilova, Martina Paumannpage, Guy N L Jameson, Anthony J KettleAbstract:Abstract Myeloperoxidase is a neutrophil enzyme that promotes oxidative stress in numerous inflammatory pathologies. It uses hydrogen peroxide to catalyze the production of strong oxidants including chlorine bleach and free radicals. A physiological defense against the inappropriate action of this enzyme has yet to be identified. We found that Myeloperoxidase oxidized 75% of the ascorbate in plasma from ceruloplasmin knock-out mice, but there was no significant loss in plasma from wild type animals. When Myeloperoxidase was added to human plasma it became bound to other proteins and was reversibly inhibited. Ceruloplasmin was the predominant protein associated with Myeloperoxidase. When the purified proteins were mixed, they became strongly but reversibly associated. Ceruloplasmin was a potent inhibitor of purified Myeloperoxidase, inhibiting production of hypochlorous acid by 50% at 25 nm. Ceruloplasmin rapidly reduced Compound I, the FeV redox intermediate of Myeloperoxidase, to Compound II, which has FeIV in its heme prosthetic groups. It also prevented the fast reduction of Compound II by tyrosine. In the presence of chloride and hydrogen peroxide, ceruloplasmin converted Myeloperoxidase to Compound II and slowed its conversion back to the ferric enzyme. Collectively, our results indicate that ceruloplasmin inhibits Myeloperoxidase by reducing Compound I and then trapping the enzyme as inactive Compound II. We propose that ceruloplasmin should provide a protective shield against inadvertent oxidant production by Myeloperoxidase during inflammation.
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Reactions of superoxide with Myeloperoxidase.
Biochemistry, 2007Co-Authors: Anthony J Kettle, Robert F Anderson, Mark B. Hampton, Christine C WinterbournAbstract:When neutrophils ingest bacteria, they discharge superoxide and Myeloperoxidase into phagosomes. Both are essential for killing of the phagocytosed micro-organisms. It is generally accepted that superoxide is a precursor of hydrogen peroxide which Myeloperoxidase uses to oxidize chloride to hypochlorous acid. Previously, we demonstrated that superoxide modulates the chlorination activity of Myeloperoxidase by reacting with its ferric and compound II redox states. In this investigation we used pulse radiolysis to determine kinetic parameters of superoxide reacting with redox forms of Myeloperoxidase and used these data in a steady-state kinetic analysis. We provide evidence that superoxide reacts with compound I and compound III. Our estimates of the rate constants for the reaction of superoxide with compound I, compound II, and compound III are 5 × 106 M-1 s-1, 5.5 ± 0.4 × 106 M-1 s-1, and 1.3 ± 0.2 × 105 M-1 s-1, respectively. These reactions define new activities for Myeloperoxidase. It will act as a su...
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modeling the reactions of superoxide and Myeloperoxidase in the neutrophil phagosome implications for microbial killing
Journal of Biological Chemistry, 2006Co-Authors: Christine C Winterbourn, Mark B. Hampton, John H Livesey, Anthony J KettleAbstract:Abstract Neutrophils kill bacteria by ingesting them into phagosomes where superoxide and cytoplasmic granule constituents, including Myeloperoxidase, are released. Myeloperoxidase converts chloride and hydrogen peroxide to hypochlorous acid (HOCl), which is strongly microbicidal. However, the role of oxidants in killing and the species responsible are poorly understood and the subject of current debate. To assess what oxidative mechanisms are likely to operate in the narrow confines of the phagosome, we have used a kinetic model to examine the fate of superoxide and its interactions with Myeloperoxidase. Known rate constants for reactions of Myeloperoxidase have been used and substrate concentrations estimated from neutrophil morphology. In the model, superoxide is generated at several mm/s. Most react with Myeloperoxidase, which is present at millimolar concentrations, and rapidly convert the enzyme to compound III. Compound III turnover by superoxide is essential to maintain enzyme activity. Superoxide stabilizes at ∼25 μm and hydrogen peroxide in the low micromolar range. HOCl production is efficient if there is adequate chloride supply, but further knowledge on chloride concentrations and transport mechanisms is needed to assess whether this is the case. Low Myeloperoxidase concentrations also limit HOCl production by allowing more hydrogen peroxide to escape from the phagosome. In the absence of Myeloperoxidase, superoxide increases to >100 μm but hydrogen peroxide to only ∼30 μm. Most of the HOCl reacts with released granule proteins before reaching the bacterium, and chloramine products may be effectors of its antimicrobial activity. Hydroxyl radicals should form only after all susceptible protein targets are consumed.
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Biomarkers of Myeloperoxidase-derived hypochlorous acid.
Free Radical Biology and Medicine, 2000Co-Authors: Christine C Winterbourn, Anthony J KettleAbstract:Abstract Hypochlorous acid is the major strong oxidant generated by neutrophils. The heme enzyme Myeloperoxidase catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride. Although Myeloperoxidase has been implicated in the tissue damage that occurs in numerous diseases that involve inflammatory cells, it has proven difficult to categorically demonstrate that it plays a crucial role in any pathology. This situation should soon be rectified with the advent of sensitive biomarkers for hypochlorous acid. In this review, we outline the advantages and limitations of chlorinated tyrosines, chlorohydrins, 5-chlorocytosine, protein carbonyls, antibodies that recognize HOCl-treated proteins, and glutathione sulfonamide as potential biomarkers of hypochlorous acid. Levels of 3-chlorotyrosine and 3,5-dichlorotyrosine are increased in proteins after exposure to low concentrations of hypochlorous acid and we conclude that their analysis by gas chromatography and mass spectrometry is currently the best method available for probing the involvement of oxidation by Myeloperoxidase in the pathology of particular diseases. The appropriate use of other biomarkers should provide complementary information. Keywords—Free radicals, Myeloperoxidase, Neutrophil oxidant, Hypochlorous acid, Chlorotyrosine, Chlorohydrin, Oxidant biomarker
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thiocyanate and chloride as competing substrates for Myeloperoxidase
Biochemical Journal, 1997Co-Authors: Christine J Van Dalen, Christine C Winterbourn, Michael W Whitehouse, Anthony J KettleAbstract:The neutrophil enzyme Myeloperoxidase uses H2O2 to oxidize chloride, bromide, iodide and thiocyanate to their respective hypohalous acids. Chloride is considered to be the physiological substrate. However, a detailed kinetic study of its substrate preference has not been undertaken. Our aim was to establish whether Myeloperoxidase oxidizes thiocyanate in the presence of chloride at physiological concentrations of these substrates. We determined this by measuring the rate of H2O2 loss in reactions catalysed by the enzyme at various concentrations of each substrate. The relative specificity constants for chloride, bromide and thiocyanate were 1:60:730 respectively, indicating that thiocyanate is by far the most favoured substrate for Myeloperoxidase. In the presence of 100 mM chloride, Myeloperoxidase catalysed the production of hypothiocyanite at concentrations of thiocyanate as low as 25 microM. With 100 microM thiocyanate, about 50% of the H2O2 present was converted into hypothiocyanite, and the rate of hypohalous acid production equalled the sum of the individual rates obtained when each of these anions was present alone. The rate of H2O2 loss catalysed by Myeloperoxidase in the presence of 100 mM chloride doubled when 100 microM thiocyanate was added, and was maximal with 1mM thiocyanate. This indicates that at plasma concentrations of thiocyanate and chloride, Myeloperoxidase is far from saturated. We conclude that thiocyanate is a major physiological substrate of Myeloperoxidase, regardless of where the enzyme acts. As a consequence, more consideration should be given to the oxidation products of thiocyanate and to the role they play in host defence and inflammation.
Marie Luise Brennan - One of the best experts on this subject based on the ideXlab platform.
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Myeloperoxidase: A mechanistically linked biomarker for cardiovascular disease
Current Cardiovascular Risk Reports, 2020Co-Authors: Marie Luise Brennan, Stanley L HazenAbstract:With increasing understanding of the cellular and molecular processes involved in atherosclerosis, new insights have been gained into the contributions of various pathways to atherosclerosis development. Myeloperoxidase, a leukocyte enzyme that is part of the innate immune response, is present, active, and believed to be functionally involved in plaque development and complications. The use of Myeloperoxidase levels in risk stratification is an example of a mechanistically linked biomarker. This review focuses on recent literature and background relevant to examining the role and potential clinical use of Myeloperoxidase in cardiovascular disease.
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serum Myeloperoxidase levels independently predict endothelial dysfunction in humans
Circulation, 2004Co-Authors: Joseph A Vita, Marie Luise Brennan, Marc S. Penn, Mehdi H. Shishehbor, Marlene Goormastic, Noyan Gokce, Shirley Mann, John F Keaney, Stanley HazenAbstract:Background— In vitro and animal studies demonstrate that Myeloperoxidase catalytically consumes nitric oxide as a substrate, limiting its bioavailability and function. We therefore hypothesized that circulating levels of Myeloperoxidase would predict risk of endothelial dysfunction in human subjects. Methods and Results— Serum Myeloperoxidase was measured by enzyme-linked immunoassay, and brachial artery flow-mediated dilation and nitroglycerin-mediated dilation were determined by ultrasound in a hospital-based population of 298 subjects participating in an ongoing study of the clinical correlates of endothelial dysfunction (age, 51±16; 61% men, 51% with cardiovascular disease). A strong inverse relation between brachial artery flow-mediated dilation and increasing quartile of serum Myeloperoxidase level was observed (11.0±6.0%, 9.4±5.3%, 8.6±5.8%, and 6.4±4.5% for quartiles 1 through 4, respectively; P<0.001 for trend). Using the median as a cut point to define endothelial dysfunction, increasing quartil...
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prognostic value of Myeloperoxidase in patients with chest pain
Obstetrical & Gynecological Survey, 2004Co-Authors: Marie Luise Brennan, Marc S. Penn, Frederick Van Lente, Vijay Nambi, Ronnier J. Aviles, Marlene Goormastic, Michael Pepoy, Ellen Mcerlean, Mehdi H Shishenbor, Eric J. TopolAbstract:The entire process of arterial plaque formation has been linked with inflammation, and extensive infiltration of neutrophils and monocytes is observed in thrombosed plaque in patients with acute coronary disease. One possible means by which leukocytes could influence the stability of plaque is Myeloperoxidase, a leukocyte enzyme that is present in elevated amounts in patients with cardiovascular disease. This study examined the possibility that plasma levels of Myeloperoxidase might serve as a marker of plaque vulnerability in patients seen in the emergency department with chest pain. The study group included 604 such patients, seen sequentially, whose most frequent final diagnoses were suspected coronary syndrome and myocardial infarction (MI). Control subjects were healthy and had no historic or clinical evidence of coronary artery disease. Enzyme levels were estimated by an enzyme-linked immunosorbent assay. Patients were seen an average of 4 hours after the onset of chest pain. Plasma Myeloperoxidase levels were significantly higher in the study group than in control subjects. They correlated weakly with peak levels of troponin T, C-reactive protein, and age, but not with white cell count. Patients having MI within 16 hours before presentation had especially high Myeloperoxidase levels, and the incidence of MI increased with increasing quartiles of Myeloperoxidase. Baseline levels were higher in patients who later required revascularization or had a major adverse cardiac event in the next 30 days or 6 months. Multivariate logistic regression analyses confirmed that elevated plasma Myeloperoxidase independently predicted an increased risk of MI, the need for revascularization, and major coronary events. Baseline levels helped to identify patients at risk even if troponin T was absent. Plasma Myeloperoxidase concentration appears to be a marker of vulnerable coronary artery plaque. It helps to identify patients at risk for major adverse cardiac events independently of evidence that myocardial necrosis is present.
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Prognostic Value of Myeloperoxidase in Patients with Chest Pain
The New England Journal of Medicine, 2003Co-Authors: Marie Luise Brennan, Marc S. Penn, Frederick Van Lente, Vijay Nambi, Mehdi H. Shishehbor, Ronnier J. Aviles, Marlene Goormastic, Michael Pepoy, Ellen Mcerlean, Eric J. TopolAbstract:background Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between Myeloperoxidase and both inflammation and cardiovascular disease. methods We assessed the value of plasma levels of Myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. results Initial plasma Myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (
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prognostic value of Myeloperoxidase in patients with chest pain
The New England Journal of Medicine, 2003Co-Authors: Marie Luise Brennan, Marc S. Penn, Frederick Van Lente, Vijay Nambi, Mehdi H. Shishehbor, Ronnier J. Aviles, Marlene Goormastic, Michael Pepoy, Ellen Mcerlean, Eric J. TopolAbstract:background Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between Myeloperoxidase and both inflammation and cardiovascular disease. methods We assessed the value of plasma levels of Myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. results Initial plasma Myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (<0.1 ng per milliliter) at base line (P< 0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (myocardial infarction, the need for revascularization, or death) within 30 days and 6 months after presentation (P<0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the base-line Myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days (unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95 percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidence interval, 2.1 to 8.4], and 4.1 [95 percent confidence interval, 2.0 to 8.4], respectively) and at 6 months. conclusions A single initial measurement of plasma Myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis, highlighting its potential usefulness for risk stratification among patients who present with chest pain.
Eric J. Topol - One of the best experts on this subject based on the ideXlab platform.
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prognostic value of Myeloperoxidase in patients with chest pain
Obstetrical & Gynecological Survey, 2004Co-Authors: Marie Luise Brennan, Marc S. Penn, Frederick Van Lente, Vijay Nambi, Ronnier J. Aviles, Marlene Goormastic, Michael Pepoy, Ellen Mcerlean, Mehdi H Shishenbor, Eric J. TopolAbstract:The entire process of arterial plaque formation has been linked with inflammation, and extensive infiltration of neutrophils and monocytes is observed in thrombosed plaque in patients with acute coronary disease. One possible means by which leukocytes could influence the stability of plaque is Myeloperoxidase, a leukocyte enzyme that is present in elevated amounts in patients with cardiovascular disease. This study examined the possibility that plasma levels of Myeloperoxidase might serve as a marker of plaque vulnerability in patients seen in the emergency department with chest pain. The study group included 604 such patients, seen sequentially, whose most frequent final diagnoses were suspected coronary syndrome and myocardial infarction (MI). Control subjects were healthy and had no historic or clinical evidence of coronary artery disease. Enzyme levels were estimated by an enzyme-linked immunosorbent assay. Patients were seen an average of 4 hours after the onset of chest pain. Plasma Myeloperoxidase levels were significantly higher in the study group than in control subjects. They correlated weakly with peak levels of troponin T, C-reactive protein, and age, but not with white cell count. Patients having MI within 16 hours before presentation had especially high Myeloperoxidase levels, and the incidence of MI increased with increasing quartiles of Myeloperoxidase. Baseline levels were higher in patients who later required revascularization or had a major adverse cardiac event in the next 30 days or 6 months. Multivariate logistic regression analyses confirmed that elevated plasma Myeloperoxidase independently predicted an increased risk of MI, the need for revascularization, and major coronary events. Baseline levels helped to identify patients at risk even if troponin T was absent. Plasma Myeloperoxidase concentration appears to be a marker of vulnerable coronary artery plaque. It helps to identify patients at risk for major adverse cardiac events independently of evidence that myocardial necrosis is present.
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Prognostic Value of Myeloperoxidase in Patients with Chest Pain
The New England Journal of Medicine, 2003Co-Authors: Marie Luise Brennan, Marc S. Penn, Frederick Van Lente, Vijay Nambi, Mehdi H. Shishehbor, Ronnier J. Aviles, Marlene Goormastic, Michael Pepoy, Ellen Mcerlean, Eric J. TopolAbstract:background Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between Myeloperoxidase and both inflammation and cardiovascular disease. methods We assessed the value of plasma levels of Myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. results Initial plasma Myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (
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prognostic value of Myeloperoxidase in patients with chest pain
The New England Journal of Medicine, 2003Co-Authors: Marie Luise Brennan, Marc S. Penn, Frederick Van Lente, Vijay Nambi, Mehdi H. Shishehbor, Ronnier J. Aviles, Marlene Goormastic, Michael Pepoy, Ellen Mcerlean, Eric J. TopolAbstract:background Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between Myeloperoxidase and both inflammation and cardiovascular disease. methods We assessed the value of plasma levels of Myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. results Initial plasma Myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (<0.1 ng per milliliter) at base line (P< 0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (myocardial infarction, the need for revascularization, or death) within 30 days and 6 months after presentation (P<0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the base-line Myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days (unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95 percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidence interval, 2.1 to 8.4], and 4.1 [95 percent confidence interval, 2.0 to 8.4], respectively) and at 6 months. conclusions A single initial measurement of plasma Myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis, highlighting its potential usefulness for risk stratification among patients who present with chest pain.
