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Antioxidants
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Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression
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Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (30 March 2024) | Viewed by 68714

Special Issue Editors

Prof. Dr. Jürgen Arnhold

E-Mail Website
Guest Editor
Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstr. 16-18, 04107 Leipzig, Germany
Interests: cell and tissue degradation; redox homeostasis; inflammatory response; termination of inflammation; disease progression; heme peroxidases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ernst Malle

E-Mail Website1 Website2
Guest Editor
Guest Scientist, Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, Bauteil K, 4. OG, 8010 Graz, Austria
Interests: antioxidants; atherosclerosis, acute-phase reaction; inflammation; native and modified (lipo)proteins; mammalian peroxidases; oxidative modifications; Serum Amyloid A (SAA)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In humans, the three heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPO), and lactoperoxidase (LPO) are essential components of immune defence against foreign microorganisms. MPO and EPO are released from activated neutrophils or eosinophils, respectively, at inflamed sites, where they contribute to killing of bacteria, fungi, and parasites. LPO contributes to inactivation of microorganisms in secretions. Furthermore, peroxidasin (PXDN), another heme peroxidase oxidizes bromide to hypobromous acid, a powerful oxidant that promotes adverse physiological alterations.

A unique property of these peroxidases is their halogenating activity and adverse modification of target compounds.

Besides the useful functions of innate immune cells in inactivation and killing of microbes, active agents released by immune cells at inflamed sites have a high potential to damage unperturbed host cells and tissues. Secreted agents from polymorphonuclear leukocytes including MPO are able to damage surrounding tissue constituents. Mechanisms determining the tight balance between helpful and harmful actions of peroxidases and immune cells are under intense investigation.

In this special issue the main focus will be the involvement of MPO, EPO, LPO and PXDN under physiological conditions and potential activities to promote disease progression. We cordially invite you to contribute to this interesting field in frame of this special issue with original research articles and/or special overviews.

Thank you very much in advance.

Prof. Dr. Jürgen Arnhold
Prof. Dr. Ernst Malle
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Disease progression
  • Eosinophil peroxidase (EPO)
  • Halogenating activity
  • Hypochlorous acid/hypochlorite (HOCl/OCl−)
  • Inflammation
  • Killing of microorganisms
  • Lactoperoxidase (LPO)
  • Myeloperoxidase (MPO)
  • Neutrophil extracellular traps (NETs)
  • Peroxidasin (PXDN)
  • Polymorphonuclear leukocytes

Published Papers (26 papers)

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20 pages, 8154 KiB  
Article
Peroxidasin Inhibition by Phloroglucinol and Other Peroxidase Inhibitors
by Martina Paumann-Page, Christian Obinger, Christine C. Winterbourn and Paul G. Furtmüller
Antioxidants 2024, 13(1), 23; https://doi.org/10.3390/antiox13010023 - 21 Dec 2023
Viewed by 986
Abstract
Human peroxidasin (PXDN) is a ubiquitous peroxidase enzyme expressed in most tissues in the body. PXDN represents an interesting therapeutic target for inhibition, as it plays a role in numerous pathologies, including cardiovascular disease, cancer and fibrosis. Like other peroxidases, PXDN generates hypohalous [...] Read more.
Human peroxidasin (PXDN) is a ubiquitous peroxidase enzyme expressed in most tissues in the body. PXDN represents an interesting therapeutic target for inhibition, as it plays a role in numerous pathologies, including cardiovascular disease, cancer and fibrosis. Like other peroxidases, PXDN generates hypohalous acids and free radical species, thereby facilitating oxidative modifications of numerous biomolecules. We have studied the inhibition of PXDN halogenation and peroxidase activity by phloroglucinol and 14 other peroxidase inhibitors. Although a number of compounds on their own potently inhibited PXDN halogenation activity, only five were effective in the presence of a peroxidase substrate with IC50 values in the low μM range. Using sequential stopped-flow spectrophotometry, we examined the mechanisms of inhibition for several compounds. Phloroglucinol was the most potent inhibitor with a nanomolar IC50 for purified PXDN and IC50 values of 0.95 μM and 1.6 μM for the inhibition of hypobromous acid (HOBr)-mediated collagen IV cross-linking in a decellularized extracellular matrix and a cell culture model. Other compounds were less effective in these models. Most interestingly, phloroglucinol was identified to irreversibly inhibit PXDN, either by mechanism-based inhibition or tight binding. Our work has highlighted phloroglucinol as a promising lead compound for the design of highly specific PXDN inhibitors and the assays used in this study provide a suitable approach for high-throughput screening of PXDN inhibitors. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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15 pages, 2863 KiB  
Article
Multi-Oxidant Environment as a Suicidal Inhibitor of Myeloperoxidase
by Ramona Clemen, Lara Minkus, Debora Singer, Paul Schulan, Thomas von Woedtke, Kristian Wende and Sander Bekeschus
Antioxidants 2023, 12(11), 1936; https://doi.org/10.3390/antiox12111936 - 30 Oct 2023
Cited by 1 | Viewed by 1091
Abstract
Tissue inflammation drives the infiltration of innate immune cells that generate reactive species to kill bacteria and recruit adaptive immune cells. Neutrophil activation fosters the release of myeloperoxidase (MPO) enzyme, a heme-containing protein generating hypochlorous acid (HOCl) from hydrogen peroxide (H2O [...] Read more.
Tissue inflammation drives the infiltration of innate immune cells that generate reactive species to kill bacteria and recruit adaptive immune cells. Neutrophil activation fosters the release of myeloperoxidase (MPO) enzyme, a heme-containing protein generating hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride ions. MPO-dependent oxidant formation initiates bioactive oxidation and chlorination products and induces oxidative post-translational modifications (oxPTMs) on proteins and lipid oxidation. Besides HOCl and H2O2, further reactive species such as singlet oxygen and nitric oxide are generated in inflammation, leading to modified proteins, potentially resulting in their altered bioactivity. So far, knowledge about multiple free radical-induced modifications of MPO and its effects on HOCl generation is lacking. To mimic this multi-oxidant microenvironment, human MPO was exposed to several reactive species produced simultaneously via argon plasma operated at body temperature. Several molecular gas admixes were used to modify the reactive species type profiles generated. MPO was investigated by studying its oxPTMs, changes in protein structure, and enzymatic activity. MPO activity was significantly reduced after treatment with all five tested plasma gas conditions. Dynamic light scattering and CD-spectroscopy revealed altered MPO protein morphology indicative of oligomerization. Using mass spectrometry, various oxPTMs, such as +1O, +2O, and +3O, were determined on methionine and cysteine (Cys), and -1H-1N+1O was detected in asparagine (Asp). The modification types identified differed between argon-oxygen and argon-nitrogen plasmas. However, all plasma gas conditions led to the deamidation of Asp and oxidation of Cys residues, suggesting an inactivation of MPO due to oxPTM-mediated conformational changes. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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17 pages, 4506 KiB  
Article
Myeloperoxidase Alters Lung Cancer Cell Function to Benefit Their Survival
by Nejra Cosic-Mujkanovic, Paulina Valadez-Cosmes, Kathrin Maitz, Anna Lueger, Zala N. Mihalic, Marah C. Runtsch, Melanie Kienzl, Michael J. Davies, Christine Y. Chuang, Akos Heinemann, Rudolf Schicho, Gunther Marsche and Julia Kargl
Antioxidants 2023, 12(8), 1587; https://doi.org/10.3390/antiox12081587 - 09 Aug 2023
Cited by 2 | Viewed by 1424
Abstract
Myeloperoxidase (MPO) is a neutrophil-derived enzyme that has been recently associated with tumour development. However, the mechanisms by which this enzyme exerts its functions remain unclear. In this study, we investigated whether myeloperoxidase can alter the function of A549 human lung cancer cells. [...] Read more.
Myeloperoxidase (MPO) is a neutrophil-derived enzyme that has been recently associated with tumour development. However, the mechanisms by which this enzyme exerts its functions remain unclear. In this study, we investigated whether myeloperoxidase can alter the function of A549 human lung cancer cells. We observed that MPO promoted the proliferation of cancer cells and inhibited their apoptosis. Additionally, it increased the phosphorylation of AKT and ERK. MPO was rapidly bound to and internalized by A549 cells, retaining its enzymatic activity. Furthermore, MPO partially translocated into the nucleus and was detected in the chromatin-enriched fraction. Effects of MPO on cancer cell function could be reduced when MPO uptake was blocked with heparin or upon inhibition of the enzymatic activity with the MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH). Lastly, we have shown that tumour-bearing mice treated with 4-ABAH had reduced tumour burden when compared to control mice. Our results highlight the role of MPO as a neutrophil-derived enzyme that can alter the function of lung cancer cells. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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14 pages, 2344 KiB  
Article
Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde
by Shubha Shakya, Reagan M. McGuffee and David A. Ford
Antioxidants 2023, 12(2), 504; https://doi.org/10.3390/antiox12020504 - 16 Feb 2023
Viewed by 1293
Abstract
Hypochlorous acid is produced by leukocyte myeloperoxidase activity. 2-Chlorofatty aldehydes (2-ClFALDs) are formed when hypochlorous acid attacks the plasma membrane phospholipid plasmalogen molecular subclass and are thus produced following leukocyte activation as well as in the lungs of mice exposed to chlorine gas. [...] Read more.
Hypochlorous acid is produced by leukocyte myeloperoxidase activity. 2-Chlorofatty aldehydes (2-ClFALDs) are formed when hypochlorous acid attacks the plasma membrane phospholipid plasmalogen molecular subclass and are thus produced following leukocyte activation as well as in the lungs of mice exposed to chlorine gas. The biological role of 2-ClFALD is largely unknown. Recently, we used an alkyne analog (2-ClHDyA) of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDA), to identify proteins covalently modified by 2-ClHDyA in endothelial cells and epithelial cells. Here, we demonstrate that 2-ClHDA reduces the metabolic activity of RAW 264.7 cells in a dose-dependent manner. 2-ClHDyA localizes to the mitochondria, endoplasmic reticulum and Golgi in RAW 264.7 cells and modifies many proteins. The thiol-containing precursor of glutathione, N-acetyl cysteine (NAC), was shown to produce an adduct with 2-ClHDA with the loss of Cl− (HDA–NAC). This adduct was characterized in both positive and negative ion modes using LC-MS/MS and electrospray ionization. NAC treatment of neutrophils reduced the 2-ClFALD levels in PMA-stimulated cells with subsequent increases in HDA–NAC. NAC treatments reduced the 2-ClHDA-elicited loss of metabolic activity in RAW 264.7 cells as well as 2-ClHDA protein modification. These studies demonstrate that 2-ClFALD toxic effects can be reduced by NAC, which reduces protein modification. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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25 pages, 4275 KiB  
Article
Hypochlorous Acid and Chloramines Induce Specific Fragmentation and Cross-Linking of the G1-IGD-G2 Domains of Recombinant Human Aggrecan, and Inhibit ADAMTS1 Activity
by Yihe Wang, Astrid Hammer, Gerald Hoefler, Ernst Malle, Clare L. Hawkins, Christine Y. Chuang and Michael J. Davies
Antioxidants 2023, 12(2), 420; https://doi.org/10.3390/antiox12020420 - 08 Feb 2023
Cited by 1 | Viewed by 1432
Abstract
Atherosclerosis is a chronic inflammatory disease and a leading cause of mortality. It is characterized by arterial wall plaques that contain high levels of cholesterol and other lipids and activated leukocytes covered by a fibrous cap of extracellular matrix (ECM). The ECM undergoes [...] Read more.
Atherosclerosis is a chronic inflammatory disease and a leading cause of mortality. It is characterized by arterial wall plaques that contain high levels of cholesterol and other lipids and activated leukocytes covered by a fibrous cap of extracellular matrix (ECM). The ECM undergoes remodelling during atherogenesis, with increased expression of aggrecan, a proteoglycan that binds low-density-lipoproteins (LDL). Aggrecan levels are regulated by proteases, including a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1). Activated leukocytes release myeloperoxidase (MPO) extracellularly, where it binds to proteins and proteoglycans. Aggrecan may therefore mediate colocalization of MPO and LDL. MPO generates hypochlorous acid (HOCl) and chloramines (RNHCl species, from reaction of HOCl with amines on amino acids and proteins) that damage LDL and proteins, but effects on aggrecan have not been examined. The present study demonstrates that HOCl cleaves truncated (G1-IGD-G2) recombinant human aggrecan at specific sites within the IGD domain, with these being different from those induced by ADAMTS1 which also cleaves within this region. Irreversible protein cross-links are also formed dose-dependently. These effects are limited by the HOCl scavenger methionine. Chloramines including those formed on amino acids, proteins, and ECM materials induce similar damage. HOCl and taurine chloramines inactivate ADAMTS1 consistent with a switch from proteolytic to oxidative aggrecan fragmentation. Evidence is also presented for colocalization of aggrecan and HOCl-generated epitopes in advanced human atherosclerotic plaques. Overall, these data show that HOCl and chloramines can induce specific modifications on aggrecan, and that these effects are distinct from those of ADAMTS1. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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22 pages, 2085 KiB  
Article
Common Reactivity and Properties of Heme Peroxidases: A DFT Study of Their Origin
by Daniel R. Ramos, Paul G. Furtmüller, Christian Obinger, Ángeles Peña-Gallego, Ignacio Pérez-Juste and J. Arturo Santaballa
Antioxidants 2023, 12(2), 303; https://doi.org/10.3390/antiox12020303 - 28 Jan 2023
Cited by 1 | Viewed by 1882
Abstract
Electronic structure calculations using the density-functional theory (DFT) have been performed to analyse the effect of water molecules and protonation on the heme group of peroxidases in different redox (ferric, ferrous, compounds I and II) and spin states. Shared geometries, spectroscopic properties at [...] Read more.
Electronic structure calculations using the density-functional theory (DFT) have been performed to analyse the effect of water molecules and protonation on the heme group of peroxidases in different redox (ferric, ferrous, compounds I and II) and spin states. Shared geometries, spectroscopic properties at the Soret region, and the thermodynamics of peroxidases are discussed. B3LYP and M06-2X density functionals with different basis sets were employed on a common molecular model of the active site (Fe-centred porphine and proximal imidazole). Computed Gibbs free energies indicate that the corresponding aquo complexes are not thermodynamically stable, supporting the five-coordinate Fe(III) centre in native ferric peroxidases, with a water molecule located at a non-bonding distance. Protonation of the ferryl oxygen of compound II is discussed in terms of thermodynamics, Fe–O bond distances, and redox properties. It is demonstrated that this protonation is necessary to account for the experimental data, and computed Gibbs free energies reveal pKa values of compound II about 8.5–9.0. Computation indicates that the general oxidative properties of peroxidase intermediates, as well as their reactivity towards water and protons and Soret bands, are mainly controlled by the iron porphyrin and its proximal histidine ligand. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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15 pages, 4191 KiB  
Article
Protective Effects of Therapeutic Neutrophil Depletion and Myeloperoxidase Inhibition on Left Ventricular Function and Remodeling in Myocardial Infarction
by Henning Guthoff, Alexander Hof, Anna Klinke, Martina Maaß, Jürgen Konradi, Dennis Mehrkens, Simon Geißen, Felix S. Nettersheim, Simon Braumann, Erik Michaelsson, Richard J. Nies, Samuel Lee, Marie-Christin Redzinski, Vera B. M. Peters, Harshal N. Nemade, Philipp von Stein, Holger Winkels, Volker Rudolph, Stephan Baldus, Matti Adam and Martin Mollenhaueradd Show full author list remove Hide full author list
Antioxidants 2023, 12(1), 33; https://doi.org/10.3390/antiox12010033 - 24 Dec 2022
Cited by 3 | Viewed by 1649
Abstract
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Improved survival has led to an increasing incidence of ischemic cardiomyopathy, making it a major reason for hospitalization in the western world. The inflammatory response in the ischemic myocardium determines the [...] Read more.
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Improved survival has led to an increasing incidence of ischemic cardiomyopathy, making it a major reason for hospitalization in the western world. The inflammatory response in the ischemic myocardium determines the extent of structural remodeling and functional deterioration, with neutrophils (PMN) being a key modulator of the propagation and resolution of inflammation. The heme enzyme myeloperoxidase (MPO) is abundantly expressed in PMN and is an important mediator of their inflammatory capacities. Here, we examine the effects of PMN reduction, MPO deficiency and MPO inhibition in two murine models of MI. Reduction in PMN count resulted in less scar formation and improved cardiac function. Similar results were obtained in genetically MPO deficient mice, suggesting that MPO is a critical factor in PMN-mediated cardiac remodeling. To test our findings in a therapeutic approach, we orally administered the MPO inhibitor AZM198 in the context of MI and could demonstrate improved cardiac function and reduced structural remodeling. Therefore, MPO appears to be a favorable pharmacological target for the prevention of long-term morbidity after MI. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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26 pages, 5654 KiB  
Article
Thiocyanate Reduces Motor Impairment in the hMPO-A53T PD Mouse Model While Reducing MPO-Oxidation of Alpha Synuclein in Enlarged LYVE1/AQP4 Positive Periventricular Glymphatic Vessels
by Wanda F. Reynolds, Ernst Malle and Richard A. Maki
Antioxidants 2022, 11(12), 2342; https://doi.org/10.3390/antiox11122342 - 26 Nov 2022
Cited by 1 | Viewed by 1601
Abstract
Parkinson’s disease (PD) is due to the oxidation of alpha synuclein (αSyn) contributing to motor impairment. We developed a transgenic mouse model of PD that overexpresses the mutated human αSyn gene (A53T) crossed to a mouse expressing the human MPO gene. This model [...] Read more.
Parkinson’s disease (PD) is due to the oxidation of alpha synuclein (αSyn) contributing to motor impairment. We developed a transgenic mouse model of PD that overexpresses the mutated human αSyn gene (A53T) crossed to a mouse expressing the human MPO gene. This model exhibits increased oxidation and chlorination of αSyn leading to greater motor impairment. In the current study, the hMPO-A53T mice were treated with thiocyanate (SCN−) which is a favored substrate of MPO as compared to chlorine. We show that hMPO-A53T mice treated with SCN− have less chlorination in the brain and show an improvement in motor skills compared to the nontreated hMPO-A53T mice. Interestingly, in the hMPO-A53T mice we found a possible link between MPO-related disease and the glymphatic system which clears waste including αSyn from the brain. The untreated hMPO-A53T mice exhibited an increase in the size of periventricular glymphatic vessels expressing the glymphatic marker LYVE1 and aquaporin 4 (AQP4). These vessels also exhibited an increase in MPO and HOCl-modified epitopes in the glymphatic vessels correlating with loss of ependymal cells lining the ventricles. These findings suggest that MPO may significantly promote the impairment of the glymphatic waste removal system thus contributing to neurodegeneration in PD. Moreover, the inhibition of MPO chlorination/oxidation by SCN− may provide a potential therapeutic approach to this disease. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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24 pages, 6673 KiB  
Article
Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity
by Oleg M. Panasenko, Viktor A. Ivanov, Elena V. Mikhalchik, Irina V. Gorudko, Daria V. Grigorieva, Liliya Yu. Basyreva, Ekaterina V. Shmeleva, Sergey A. Gusev, Valeria A. Kostevich, Nikolay P. Gorbunov and Alexey V. Sokolov
Antioxidants 2022, 11(11), 2263; https://doi.org/10.3390/antiox11112263 - 16 Nov 2022
Cited by 4 | Viewed by 1936
Abstract
Hyperglycemia in diabetes mellitus induces modification of proteins by glucose and its derivative methylglyoxal (MG). Neutrophils perform their bactericidal activity mainly via reactive halogen (RHS) and oxygen (ROS) species generation catalyzed by myeloperoxidase (MPO) stored in neutrophil azurophilic granules (AGs) and membrane NADPH [...] Read more.
Hyperglycemia in diabetes mellitus induces modification of proteins by glucose and its derivative methylglyoxal (MG). Neutrophils perform their bactericidal activity mainly via reactive halogen (RHS) and oxygen (ROS) species generation catalyzed by myeloperoxidase (MPO) stored in neutrophil azurophilic granules (AGs) and membrane NADPH oxidase, respectively. Herein, we study the binding of human serum albumin (HSA) modified with MG (HSA-MG) to MPO and its effects on MPO activity and release by neutrophils. Peroxidase activity of MPO was registered by oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, and chlorinating activity by decolorization of Celestine blue B dye. Binding of HSA-MG to MPO was studied by affinity chromatography, disc-electrophoresis, ligand Western blotting and enzyme-linked solid phase immunoassay using monoclonal antibodies (mAbs) to MPO. ROS and RHS generation were detected by lucigenin (Luc) and luminol (Lum) chemiluminescence (CL), respectively. Neutrophil degranulation was assessed by flow cytometry using fluorescent labeled antibodies to the marker proteins CD63 from AGs and CD11b from peroxidase-negative granules (PNGs). NETosis was assayed by quantifying DNA network-like structures (NET-like structures) in blood smears stained by Romanowsky. HSA-MG bound to MPO, giving a stable complex (Kd = 1.5 nM) and competing with mAbs, and non-competitively inhibited peroxidase and chlorinating MPO activity and induced degranulation of PNGs but not of AGs. HSA-MG enhanced Luc-CL per se or following PMA, unlike Lum-CL, and did not affect spontaneous or PMA-stimulated NETosis. Thus, HSA modified under hyperglycemia-like conditions stimulated NADPH oxidase of neutrophils but dampened their functions dependent on activity of MPO, with no effect on its release via degranulation or NETosis. This phenomenon could underlie the downregulation of bactericidal activity of MPO and neutrophils, and hence of innate immunity, giving rise to wound healing impairment and susceptibility to infection in patients with hyperglycemia. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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15 pages, 3351 KiB  
Article
New Application of the Commercially Available Dye Celestine Blue B as a Sensitive and Selective Fluorescent “Turn-On” Probe for Endogenous Detection of HOCl and Reactive Halogenated Species
by Veronika E. Reut, Stanislav O. Kozlov, Igor V. Kudryavtsev, Natalya A. Grudinina, Valeria A. Kostevich, Nikolay P. Gorbunov, Daria V. Grigorieva, Julia A. Kalvinkovskaya, Sergey B. Bushuk, Elena Yu Varfolomeeva, Natalia D. Fedorova, Irina V. Gorudko, Oleg M. Panasenko, Vadim B. Vasilyev and Alexey V. Sokolov
Antioxidants 2022, 11(9), 1719; https://doi.org/10.3390/antiox11091719 - 30 Aug 2022
Cited by 3 | Viewed by 2571
Abstract
Hypochlorous acid (HOCl) derived from hydrogen peroxide and chloride anion by myeloperoxidase (MPO) plays a significant role in physiological and pathological processes. Herein we report a phenoxazine-based fluorescent probe Celestine Blue B (CB) that is applicable for HOCl detection in living cells and [...] Read more.
Hypochlorous acid (HOCl) derived from hydrogen peroxide and chloride anion by myeloperoxidase (MPO) plays a significant role in physiological and pathological processes. Herein we report a phenoxazine-based fluorescent probe Celestine Blue B (CB) that is applicable for HOCl detection in living cells and for assaying the chlorinating activity of MPO. A remarkable selectivity and sensitivity (limit of detection is 32 nM), along with a rapid “turn-on” response of CB to HOCl was demonstrated. Furthermore, the probe was able to detect endogenous HOCl and reactive halogenated species by fluorescence spectroscopy, confocal microscopy, and flow cytometry techniques. Hence, CB is a promising tool for investigating the role of HOCl in health and disease and for screening the drugs capable of regulating MPO activity. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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22 pages, 4583 KiB  
Article
Activation and Inhibition of Human Matrix Metalloproteinase-9 (MMP9) by HOCl, Myeloperoxidase and Chloramines
by Yihe Wang, Christine Y. Chuang, Clare L. Hawkins and Michael J. Davies
Antioxidants 2022, 11(8), 1616; https://doi.org/10.3390/antiox11081616 - 20 Aug 2022
Cited by 4 | Viewed by 2336
Abstract
Matrix metalloproteinase-9 (MMP9, gelatinase B) plays a key role in the degradation of extracellular-matrix (ECM) proteins in both normal physiology and multiple pathologies, including those linked with inflammation. MMP9 is excreted as an inactive proform (proMMP9) by multiple cells, and particularly neutrophils. The [...] Read more.
Matrix metalloproteinase-9 (MMP9, gelatinase B) plays a key role in the degradation of extracellular-matrix (ECM) proteins in both normal physiology and multiple pathologies, including those linked with inflammation. MMP9 is excreted as an inactive proform (proMMP9) by multiple cells, and particularly neutrophils. The proenzyme undergoes subsequent processing to active forms, either enzymatically (e.g., via plasmin and stromelysin-1/MMP3), or via the oxidation of a cysteine residue in the prodomain (the “cysteine-switch”). Activated leukocytes, including neutrophils, generate O2− and H2O2 and release myeloperoxidase (MPO), which catalyzes hypochlorous acid (HOCl) formation. Here, we examine the reactivity of HOCl and a range of low-molecular-mass and protein chloramines with the pro- and activated forms of MMP9. HOCl and an enzymatic MPO/H2O2/Cl− system were able to generate active MMP9, as determined by fluorescence-activity assays and gel zymography. The inactivation of active MMP9 also occurred at high HOCl concentrations. Low (nM—low μM) concentrations of chloramines formed by the reaction of HOCl with amino acids (taurine, lysine, histidine), serum albumin, ECM proteins (laminin and fibronectin) and basement membrane extracts (but not HEPES chloramines) also activate proMMP9. This activation is diminished by the competitive HOCl-reactive species, methionine. These data indicate that HOCl-mediated oxidation and MMP-mediated ECM degradation are synergistic and interdependent. As previous studies have shown that modified ECM proteins can also stimulate the cellular expression of MMP proteins, these processes may contribute to a vicious cycle of increasing ECM degradation during disease development. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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14 pages, 3643 KiB  
Article
The Use of Thiocyanate Formulations to Create Manganese Porphyrin Antioxidants That Supplement Innate Immunity
by Brian J. Day, Elysia Min, Jie Huang and Chris Stanley
Antioxidants 2022, 11(7), 1252; https://doi.org/10.3390/antiox11071252 - 25 Jun 2022
Cited by 1 | Viewed by 1382
Abstract
The innate immune response to infection results in inflammation and oxidative damage, creating a paradox where most anti-inflammatory and antioxidant therapies can further suppress an already inadequate immune response. We have previously reported the beneficial effects of the exogenous supplementation of innate immunity [...] Read more.
The innate immune response to infection results in inflammation and oxidative damage, creating a paradox where most anti-inflammatory and antioxidant therapies can further suppress an already inadequate immune response. We have previously reported the beneficial effects of the exogenous supplementation of innate immunity with small pseudohalide thiocyanate (−SCN) in a mouse model of a cystic fibrosis (CF) lung infection and inflammation. The object of this study was to evaluate the use of −SCN as a counter anion for cationic manganese porphyrin (MnP) catalytic antioxidants, which could increase the parent compound’s antioxidant spectrum against hypohalous acids while supplementing innate immunity. The antioxidant activities of the parent compound were examined, as its chloride salt was compared with the −SCN-anion exchanged compound, (MnP(SCN) versus MnP(Cl)). We measured the superoxide dismutase activity spectrophotometrically and performed hydrogen peroxide scavenging using oxygen and hydrogen peroxide electrodes. Peroxidase activity was measured using an amplex red assay. The inhibition of lipid peroxidation was assessed using a thiobarbituric acid reactive species (TBARS) assay. The effects of the MnP compounds on macrophage phagocytosis were assessed by flow cytometry. The abilities of the MnP(Cl) formulations to protect human bronchiolar epithelial cells against hypochlorite (HOCl) and glycine chloramine versus their MnP(SCN) formulations were assessed using a cell viability assay. We found that anions exchanging out the chloride for −SCN improved the cellular bioavailability but did not adversely affect the cell viability or phagocytosis and that they switched hydrogen-peroxide scavenging from a dismutation reaction to a peroxidase reaction. In addition, the −SCN formulations improved the ability of MnPs to protect human bronchiolar epithelial cells against hypochlorous acid (HOCl) and glycine chloramine toxicity. These novel types of antioxidants may be more beneficial in treating lung disease that is associated with chronic infections or acute infectious exacerbations. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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20 pages, 2808 KiB  
Article
Uric Acid Reacts with Peroxidasin, Decreases Collagen IV Crosslink, Impairs Human Endothelial Cell Migration and Adhesion
by Bianca Dempsey, Litiele Cezar Cruz, Marcela Franco Mineiro, Railmara Pereira da Silva and Flavia Carla Meotti
Antioxidants 2022, 11(6), 1117; https://doi.org/10.3390/antiox11061117 - 04 Jun 2022
Cited by 6 | Viewed by 2644
Abstract
Uric acid is considered the main substrate for peroxidases in plasma. The oxidation of uric acid by human peroxidases generates urate free radical and urate hydroperoxide, which might affect endothelial function and explain, at least in part, the harmful effects of uric acid [...] Read more.
Uric acid is considered the main substrate for peroxidases in plasma. The oxidation of uric acid by human peroxidases generates urate free radical and urate hydroperoxide, which might affect endothelial function and explain, at least in part, the harmful effects of uric acid on the vascular system. Peroxidasin (PXDN), the most recent heme-peroxidase described in humans, catalyzes the formation of hypobromous acid, which mediates collagen IV crosslinks in the extracellular matrix. This enzyme has gained increasing scientific interest since it is associated with cardiovascular disease, cancer, and renal fibrosis. The main objective here was to investigate whether uric acid would react with PXDN and compromise the function of the enzyme in human endothelial cells. Urate decreased Amplex Red oxidation and brominating activity in the extracellular matrix (ECM) from HEK293/PXDN overexpressing cells and in the secretome of HUVECs. Parallelly, urate was oxidized to 5-hydroxyisourate. It also decreased collagen IV crosslink in isolated ECM from PFHR9 cells. Urate, the PXDN inhibitor phloroglucinol, and the PXDN knockdown impaired migration and adhesion of HUVECs. These results demonstrated that uric acid can affect extracellular matrix formation by competing for PXDN. The oxidation of uric acid by PXDN is likely a relevant mechanism in the endothelial dysfunction related to this metabolite. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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16 pages, 3969 KiB  
Article
Endothelial Cell Protein Targeting by Myeloperoxidase-Derived 2-Chlorofatty Aldehyde
by Shubha Shakya, Roger A. Herr, Haley L. Carlson, Raphael A. Zoeller, Carolyn J. Albert and David A. Ford
Antioxidants 2022, 11(5), 940; https://doi.org/10.3390/antiox11050940 - 10 May 2022
Cited by 3 | Viewed by 3752
Abstract
Neutrophils are important cellular mediators of injury and repair in diseases including ischemic heart disease, atherosclerosis, and sepsis. Myeloperoxidase-derived (MPO)-oxidants released from neutrophils are potential mediators of endothelial injury in disease. MPO-derived HOCl attacks plasmalogen phospholipid to liberate 2-chlorofatty aldehyde (2-ClFALD). Both 2-ClFALD [...] Read more.
Neutrophils are important cellular mediators of injury and repair in diseases including ischemic heart disease, atherosclerosis, and sepsis. Myeloperoxidase-derived (MPO)-oxidants released from neutrophils are potential mediators of endothelial injury in disease. MPO-derived HOCl attacks plasmalogen phospholipid to liberate 2-chlorofatty aldehyde (2-ClFALD). Both 2-ClFALD and its oxidation product, 2-chlorofatty acid (2-ClFA), are electrophilic lipids, and both probably react with proteins through several mechanisms. In the present study, we investigate protein modification specifically by 2-ClFALD under non-reducing conditions (e.g., without stabilizing Schiff base bonds), which likely reflects nucleophilic targeting of the electrophilic chlorinated carbon. Protein modification by the ω-alkyne analog of 2-chlorohexadecanal (2-ClHDA), 2-ClHDyA, was compared to that with the ω-alkyne analog of 2-chlorohexadecanoic acid (2-ClHA), 2-ClHyA, in multiple cell lines, which demonstrated 2-ClFALD preferentially modifies proteins compared to 2-ClFA. The 2-ClHDyA modified proteins from EA.hy926 cells and human lung microvascular endothelial cells analyzed by shotgun proteomics and over-representation analysis included adherens junction, cell adhesion molecule binding, and cell substrate junction enrichment categories. It is possible that proteins in these groups may have roles in previously described 2-ClFALD-elicited endothelial barrier dysfunction. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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13 pages, 2588 KiB  
Article
Natural Polyphenols May Normalize Hypochlorous Acid-Evoked Hemostatic Abnormalities in Human Blood
by Tomasz Misztal, Agata Golaszewska, Natalia Marcińczyk, Maria Tomasiak-Łozowska, Małgorzata Szymanowska, Ewa Chabielska and Tomasz Rusak
Antioxidants 2022, 11(4), 779; https://doi.org/10.3390/antiox11040779 - 14 Apr 2022
Cited by 1 | Viewed by 1763
Abstract
During pathogen invasion, activated neutrophils secrete myeloperoxidase (MPO), which generates high local concentrations of hypochlorous acid (HOCl), a strong antimicrobial agent. Prolonged or uncontrolled HOCl production may, however, affect hemostasis, manifesting in inhibition of platelet aggregation and thrombus formation and in elevated fibrin [...] Read more.
During pathogen invasion, activated neutrophils secrete myeloperoxidase (MPO), which generates high local concentrations of hypochlorous acid (HOCl), a strong antimicrobial agent. Prolonged or uncontrolled HOCl production may, however, affect hemostasis, manifesting in inhibition of platelet aggregation and thrombus formation and in elevated fibrin density and attenuated fibrinolysis. In this report, we investigated whether three plant-derived polyphenols with well-known antioxidant properties, i.e., quercetin (Que), epigallocatechin gallate (EGCG), and resveratrol (Resv), at concentrations not affecting platelet responses per se, may normalize particular aspects of hemostasis disturbed by HOCl. Specifically, Que (5–25 μM) and EGCG (10–25 μM) abolished HOCl-evoked inhibition of platelet aggregation (assessed by an optical method), while the simultaneous incubation of platelet-rich plasma with Resv (10–25 μM) enhanced the inhibitory effect of HOCl. A similar effect was observed in the case of thrombus formation under flow conditions, evaluated in whole blood by confocal microscope. When plasma samples were incubated with HOCl, a notably higher density of fibrin (recorded by confocal microscope) was detected, an effect that was efficiently normalized by Que (5–25 μM), EGCG (10–25 μM), and Resv (5–25 μM) and which corresponded with the normalization of the HOCl-evoked prolongation of fibrinolysis, measured in plasma by a turbidimetric method. In conclusion, this report indicates that supplementation with Que and EGCG may be helpful in the normalization of hemostatic abnormalities during inflammatory states associated with elevated HOCl production, while the presence of Resv enhances the inhibitory action of HOCl towards platelets. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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14 pages, 2335 KiB  
Article
Haloperoxidase-Catalyzed Luminol Luminescence
by Robert C. Allen
Antioxidants 2022, 11(3), 518; https://doi.org/10.3390/antiox11030518 - 08 Mar 2022
Cited by 1 | Viewed by 5125
Abstract
Common peroxidase action and haloperoxidase action are quantifiable as light emission from dioxygenation of luminol (5-amino-2,3-dihydrophthalazine-1,4-dione). The velocity of enzyme action is dependent on the concentration of reactants. Thus, the reaction order of each participant reactant in luminol luminescence was determined. Horseradish peroxidase [...] Read more.
Common peroxidase action and haloperoxidase action are quantifiable as light emission from dioxygenation of luminol (5-amino-2,3-dihydrophthalazine-1,4-dione). The velocity of enzyme action is dependent on the concentration of reactants. Thus, the reaction order of each participant reactant in luminol luminescence was determined. Horseradish peroxidase (HRP)-catalyzed luminol luminescence is first order for hydrogen peroxide (H2O2), but myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are second order for H2O2. For MPO, reaction is first order for chloride (Cl−) or bromide (Br−). For EPO, reaction is first order for Br−. HRP action has no halide requirement. For MPO and EPO, reaction is first order for luminol, but for HRP, reaction is greater than first order for luminol. Haloperoxidase-catalyzed luminol luminescence requires acidity, but HRP action requires alkalinity. Unlike the radical mechanism of common peroxidase, haloperoxidases (XPO) catalyze non-radical oxidation of halide to hypohalite. That reaction is second order for H2O2 is consistent with the non-enzymatic reaction of hypohalite with a second H2O2 to produce singlet molecular oxygen (1O2*) for luminol dioxygenation. Alternatively, luminol dehydrogenation by hypohalite followed by reaction with H2O2 yields dioxygenation consistent with the same reaction order. Haloperoxidase action, Cl−, and Br− are specifically quantifiable as luminol luminescence in an acidic milieu. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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21 pages, 2266 KiB  
Article
Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes
by Chintan N. Koyani, Susanne Scheruebel, Ge Jin, Ewald Kolesnik, Klaus Zorn-Pauly, Heinrich Mächler, Gerald Hoefler, Dirk von Lewinski, Frank R. Heinzel, Brigitte Pelzmann and Ernst Malle
Antioxidants 2022, 11(1), 25; https://doi.org/10.3390/antiox11010025 - 23 Dec 2021
Cited by 5 | Viewed by 2727
Abstract
Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades [...] Read more.
Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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19 pages, 5007 KiB  
Article
Neutrophil NET Formation with Microbial Stimuli Requires Late Stage NADPH Oxidase Activity
by Heather A. Parker, Harry M. Jones, Christopher D. Kaldor, Mark B. Hampton and Christine C. Winterbourn
Antioxidants 2021, 10(11), 1791; https://doi.org/10.3390/antiox10111791 - 09 Nov 2021
Cited by 4 | Viewed by 1750
Abstract
Neutrophils respond to a range of stimuli by releasing extracellular traps (NETs), a mesh consisting of chromatin plus granule and cytoplasmic proteins. We have investigated NET release in response to phorbol myristate acetate (PMA), Pseudomonas aeruginosa (PAO1), Staphylococcus aureus and Candida albicans, [...] Read more.
Neutrophils respond to a range of stimuli by releasing extracellular traps (NETs), a mesh consisting of chromatin plus granule and cytoplasmic proteins. We have investigated NET release in response to phorbol myristate acetate (PMA), Pseudomonas aeruginosa (PAO1), Staphylococcus aureus and Candida albicans, and the involvement of NADPH oxidase (NOX2) and myeloperoxidase (MPO) activities. An oxidative mechanism was involved with each stimulus, and the NOX2 inhibitor diphenylene iodonium (DPI) gave almost total inhibition. Notably, DPI added up to 60–90 min after stimulation still gave significant inhibition of subsequent NET formation. As most of the NOX2 activity had already occurred by that time, this indicates a requirement for late-stage low-level oxidant production. Inhibition of histone citrullination did not suppress NET formation, indicating that this was not the essential oxidant-dependent step. With PMA and P. aeruginosa PAO1, MPO activity played an important role in the induction of NETs and MPO inhibitors added up to 30–90 min after stimulation suppressed NET formation. NET formation with S. aureus and C. albicans was insensitive to MPO inhibition. Thus, MPO products are important with some stimuli but not others. Our results extend earlier observations with PMA and show that induction of NETs by microbial stimuli requires late stage oxidant production. Others have shown that NET formation involves NOX2-dependent elastase release from granules. As this is an early event, we conclude from our results that there is more than one oxidant-dependent step. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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14 pages, 2731 KiB  
Article
Reverse Ordered Sequential Mechanism for Lactoperoxidase with Inhibition by Hydrogen Peroxide
by Kellye Cupp-Sutton and Michael T. Ashby
Antioxidants 2021, 10(11), 1646; https://doi.org/10.3390/antiox10111646 - 20 Oct 2021
Cited by 4 | Viewed by 1878
Abstract
Lactoperoxidase (LPO, FeIII in its resting state in the absence of substrates)—an enzyme secreted from human mammary, salivary, and other mucosal glands—catalyzes the oxidation of thiocyanate (SCN−) by hydrogen peroxide (H2O2) to produce hypothiocyanite (OSCN− [...] Read more.
Lactoperoxidase (LPO, FeIII in its resting state in the absence of substrates)—an enzyme secreted from human mammary, salivary, and other mucosal glands—catalyzes the oxidation of thiocyanate (SCN−) by hydrogen peroxide (H2O2) to produce hypothiocyanite (OSCN−), which functions as an antimicrobial agent. The accepted catalytic mechanism, called the halogen cycle, comprises a two-electron oxidation of LPO by H2O2 to produce oxoiron(IV) radicals, followed by O-atom transfer to SCN−. However, the mechanism does not explain biphasic kinetics and inhibition by H2O2 at low concentration of reducing substrate, conditions that may be biologically relevant. We propose an ordered sequential mechanism in which the order of substrate binding is reversed, first SCN− and then H2O2. The sequence of substrate binding that is described by the halogen cycle mechanism is actually inhibitory. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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17 pages, 2731 KiB  
Article
Characterization of the Proprotein Convertase-Mediated Processing of Peroxidasin and Peroxidasin-like Protein
by Hajnal A. Kovács, Enikő Lázár, György Várady, Gábor Sirokmány and Miklós Geiszt
Antioxidants 2021, 10(10), 1565; https://doi.org/10.3390/antiox10101565 - 30 Sep 2021
Cited by 6 | Viewed by 2142
Abstract
Peroxidasin (PXDN) and peroxidasin-like protein (PXDNL) are members of the peroxidase-cyclooxygenase superfamily. PXDN functions in basement membrane synthesis by forming collagen IV crosslinks, while the function of PXDNL remains practically unknown. In this work, we characterized the post-translational proteolytic processing of PXDN and [...] Read more.
Peroxidasin (PXDN) and peroxidasin-like protein (PXDNL) are members of the peroxidase-cyclooxygenase superfamily. PXDN functions in basement membrane synthesis by forming collagen IV crosslinks, while the function of PXDNL remains practically unknown. In this work, we characterized the post-translational proteolytic processing of PXDN and PXDNL. Using a novel knock-in mouse model, we demonstrate that the proteolytic cleavage of PXDN occurs in vivo. With the help of furin-specific siRNA we also demonstrate that the proprotein-convertase, furin participates in the proteolytic processing of PXDN. Furthermore, we demonstrate that only the proteolytically processed PXDN integrates into the extracellular matrix, highlighting the importance of the proteolysis step in PXDN’s collagen IV-crosslinking activity. We also provide multiple lines of evidence for the importance of peroxidase activity in the proteolytic processing of PXDN. Finally, we show that PXDNL does not undergo proteolytic processing, despite containing sequence elements efficiently recognized by proprotein convertases. Collectively, our observations suggest a previously unknown protein quality control during PXDN synthesis and the importance of the peroxidase activity of PXDN in this process. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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15 pages, 6748 KiB  
Article
Myeloperoxidase Inhibition Ameliorates Plaque Psoriasis in Mice
by Savannah D. Neu, Anna Strzepa, Dustin Martin, Mary G. Sorci-Thomas, Kirkwood A. Pritchard, Jr. and Bonnie N. Dittel
Antioxidants 2021, 10(9), 1338; https://doi.org/10.3390/antiox10091338 - 25 Aug 2021
Cited by 8 | Viewed by 3361
Abstract
Plaque psoriasis is a common inflammatory condition of the skin characterized by red, flaking lesions. Current therapies for plaque psoriasis target many facets of the autoimmune response, but there is an incomplete understanding of how oxidative damage produced by enzymes such as myeloperoxidase [...] Read more.
Plaque psoriasis is a common inflammatory condition of the skin characterized by red, flaking lesions. Current therapies for plaque psoriasis target many facets of the autoimmune response, but there is an incomplete understanding of how oxidative damage produced by enzymes such as myeloperoxidase contributes to skin pathology. In this study, we used the Aldara (Imiquimod) cream model of plaque psoriasis in mice to assess myeloperoxidase inhibition for treating psoriatic skin lesions. To assess skin inflammation severity, an innovative mouse psoriasis scoring system was developed. We found that myeloperoxidase inhibition ameliorated psoriasis severity when administered either systemically or topically. The findings of this study support the role of oxidative damage in plaque psoriasis pathology and present potential new therapeutic avenues for further exploration. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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Review

Jump to: Research

21 pages, 701 KiB  
Review
Myeloperoxidase: Regulation of Neutrophil Function and Target for Therapy
by Salma A. Rizo-Téllez, Meriem Sekheri and János G. Filep
Antioxidants 2022, 11(11), 2302; https://doi.org/10.3390/antiox11112302 - 21 Nov 2022
Cited by 20 | Viewed by 5864
Abstract
Neutrophils, the most abundant white blood cells in humans, are critical for host defense against invading pathogens. Equipped with an array of antimicrobial molecules, neutrophils can eradicate bacteria and clear debris. Among the microbicide proteins is the heme protein myeloperoxidase (MPO), stored in [...] Read more.
Neutrophils, the most abundant white blood cells in humans, are critical for host defense against invading pathogens. Equipped with an array of antimicrobial molecules, neutrophils can eradicate bacteria and clear debris. Among the microbicide proteins is the heme protein myeloperoxidase (MPO), stored in the azurophilic granules, and catalyzes the formation of the chlorinating oxidant HOCl and other oxidants (HOSCN and HOBr). MPO is generally associated with killing trapped bacteria and inflicting collateral tissue damage to the host. However, the characterization of non-enzymatic functions of MPO suggests additional roles for this protein. Indeed, evolving evidence indicates that MPO can directly modulate the function and fate of neutrophils, thereby shaping immunity. These actions include MPO orchestration of neutrophil trafficking, activation, phagocytosis, lifespan, formation of extracellular traps, and MPO-triggered autoimmunity. This review scrutinizes the multifaceted roles of MPO in immunity, focusing on neutrophil-mediated host defense, tissue damage, repair, and autoimmunity. We also discuss novel therapeutic approaches to target MPO activity, expression, or MPO signaling for the treatment of inflammatory and autoimmune diseases. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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28 pages, 10743 KiB  
Review
Halogenation Activity of Mammalian Heme Peroxidases
by Jürgen Arnhold and Ernst Malle
Antioxidants 2022, 11(5), 890; https://doi.org/10.3390/antiox11050890 - 30 Apr 2022
Cited by 15 | Viewed by 2455
Abstract
Mammalian heme peroxidases are fascinating due to their unique peculiarity of oxidizing (pseudo)halides under physiologically relevant conditions. These proteins are able either to incorporate oxidized halides into substrates adjacent to the active site or to generate different oxidized (pseudo)halogenated species, which can take [...] Read more.
Mammalian heme peroxidases are fascinating due to their unique peculiarity of oxidizing (pseudo)halides under physiologically relevant conditions. These proteins are able either to incorporate oxidized halides into substrates adjacent to the active site or to generate different oxidized (pseudo)halogenated species, which can take part in multiple (pseudo)halogenation and oxidation reactions with cell and tissue constituents. The present article reviews basic biochemical and redox mechanisms of (pseudo)halogenation activity as well as the physiological role of heme peroxidases. Thyroid peroxidase and peroxidasin are key enzymes for thyroid hormone synthesis and the formation of functional cross-links in collagen IV during basement membrane formation. Special attention is directed to the properties, enzymatic mechanisms, and resulting (pseudo)halogenated products of the immunologically relevant proteins such as myeloperoxidase, eosinophil peroxidase, and lactoperoxidase. The potential role of the (pseudo)halogenated products (hypochlorous acid, hypobromous acid, hypothiocyanite, and cyanate) of these three heme peroxidases is further discussed. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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14 pages, 673 KiB  
Review
Unexpected Role of MPO-Oxidized LDLs in Atherosclerosis: In between Inflammation and Its Resolution
by Cecilia Tangeten, Karim Zouaoui Boudjeltia, Cedric Delporte, Pierre Van Antwerpen and Keziah Korpak
Antioxidants 2022, 11(5), 874; https://doi.org/10.3390/antiox11050874 - 28 Apr 2022
Cited by 8 | Viewed by 2783
Abstract
Inflammation and its resolution are the result of the balance between pro-inflammatory and pro-resolving factors, such as specialized pro-resolving mediators (SPMs). This balance is crucial for plaque evolution in atherosclerosis, a chronic inflammatory disease. Myeloperoxidase (MPO) has been related to oxidative stress and [...] Read more.
Inflammation and its resolution are the result of the balance between pro-inflammatory and pro-resolving factors, such as specialized pro-resolving mediators (SPMs). This balance is crucial for plaque evolution in atherosclerosis, a chronic inflammatory disease. Myeloperoxidase (MPO) has been related to oxidative stress and atherosclerosis, and MPO-oxidized low-density lipoproteins (Mox-LDLs) have specific characteristics and effects. They participate in foam cell formation and cause specific reactions when interacting with macrophages and endothelial cells. They also increase the production of intracellular reactive oxygen species (ROS) in macrophages and the resulting antioxidant response. Mox-LDLs also drive macrophage polarization. Mox-LDLs are known to be pro-inflammatory particles. However, in the presence of Mox-LDLs, endothelial cells produce resolvin D1 (RvD1), a SPM. SPMs are involved in the resolution of inflammation by stimulating efferocytosis and by reducing the adhesion and recruitment of neutrophils and monocytes. RvD1 also induces the synthesis of other SPMs. In vitro, Mox-LDLs have a dual effect by promoting RvD1 release and inducing a more anti-inflammatory phenotype macrophage, thereby having a mixed effect on inflammation. In this review, we discuss the interrelationship between MPO, Mox-LDLs, and resolvins, highlighting a new perception of the role of Mox-LDLs in atherosclerosis. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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20 pages, 1564 KiB  
Review
Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies
by Gunther Marsche, Julia T. Stadler, Julia Kargl and Michael Holzer
Antioxidants 2022, 11(3), 556; https://doi.org/10.3390/antiox11030556 - 15 Mar 2022
Cited by 8 | Viewed by 3128
Abstract
Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as [...] Read more.
Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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20 pages, 701 KiB  
Review
Heme Peroxidases at Unperturbed and Inflamed Mucous Surfaces
by Jürgen Arnhold
Antioxidants 2021, 10(11), 1805; https://doi.org/10.3390/antiox10111805 - 12 Nov 2021
Cited by 10 | Viewed by 3547
Abstract
In our organism, mucous surfaces are important boundaries against the environmental milieu with defined fluxes of metabolites through these surfaces and specific rules for defense reactions. Major mucous surfaces are formed by epithelia of the respiratory system and the digestive tract. The heme [...] Read more.
In our organism, mucous surfaces are important boundaries against the environmental milieu with defined fluxes of metabolites through these surfaces and specific rules for defense reactions. Major mucous surfaces are formed by epithelia of the respiratory system and the digestive tract. The heme peroxidases lactoperoxidase (LPO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO) contribute to immune protection at epithelial surfaces and in secretions. Whereas LPO is secreted from epithelial cells and maintains microbes in surface linings on low level, MPO and EPO are released from recruited neutrophils and eosinophils, respectively, at inflamed mucous surfaces. Activated heme peroxidases are able to oxidize (pseudo)halides to hypohalous acids and hypothiocyanite. These products are involved in the defense against pathogens, but can also contribute to cell and tissue damage under pathological conditions. This review highlights the beneficial and harmful functions of LPO, MPO, and EPO at unperturbed and inflamed mucous surfaces. Among the disorders, special attention is directed to cystic fibrosis and allergic reactions. Full article
(This article belongs to the Special Issue Heme Peroxidases in (Patho)Physiological Reactions and Disease Progression)
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