MPO (Myeloperoxidase) Caused Endothelial Dysfunction
2018; Lippincott Williams & Wilkins; Volume: 38; Issue: 8 Linguagem: Inglês
10.1161/atvbaha.118.311427
ISSN1524-4636
AutoresCeline L. Hartman, David A. Ford,
Tópico(s)Medical and Biological Ozone Research
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 38, No. 8MPO (Myeloperoxidase) Caused Endothelial Dysfunction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMPO (Myeloperoxidase) Caused Endothelial DysfunctionNot So Positive It Is About the Bleach, It May Be a Fatal Attraction Celine L. Hartman and David A. Ford Celine L. HartmanCeline L. Hartman and David A. FordDavid A. Ford Correspondence to David A. Ford, PhD, Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 Grand Ave, DRC 325, St. Louis, MO 63104. E-mail E-mail Address: [email protected] Originally published25 Jul 2018https://doi.org/10.1161/ATVBAHA.118.311427Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:1676–1677This article is a commentary on the followingMPO (Myeloperoxidase) Reduces Endothelial Glycocalyx Thickness Dependent on Its Cationic ChargeOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 25, 2018: Previous Version of Record MPO (myeloperoxidase) was first described as a highly abundant protein in neutrophils in 1941.1 In 1958, MPO was purified,2 but the function remained unknown. Over the next decade, studies revealed the mechanisms of degranulation3 and reactive oxygen species production4 by neutrophils during phagocytosis. A series of pivotal studies in 1967 and 1968 by Klebanoff5–7 proposed the classical role of MPO in phagocytosis, suggesting that the MPO-halide-H2O2 system is a powerful antimicrobial mechanism. Highly reactive products of this system, including HOCl, are short-lived and react rapidly with any oxidizable group to kill pathogens during phagocytosis. Less reactive products, including H2O2 and some chloramines, can travel to be toxic at a distant site. Because MPO is a strongly basic protein and can bind to surface of a negatively charged cell, this potentially allows for continuous propagation of the antimicrobial response.See accompanying article on page 1859In contrast to the classical role of MPO, there has been significant evidence that MPO can damage host tissue and contribute to human disease, specifically those that involve damage to the endothelium in the vasculature. Leukocyte-endothelial interactions are critically regulated to maintain macro- and microvascular health. Leukocyte MPO traditionally has been considered as a robust oxidation system that potentially has deleterious effects at the blood-endothelial interface, as well as the subendothelial space. Leukocyte interaction with the endothelium first involves an encounter with the endothelial glycocalyx. MPO has been shown to be released at or near the glycocalyx, accumulate along the endothelium, and be transported across endothelial cells.8 MPO targets extracellular matrix proteins,9 reduces NO availability,10,11 and mediates neutrophil recruitment and activation12,13 (Figure). MPO plays a role in renal disease,14 sickle cell disease,15 ischemia/reperfusion injury,16 atherosclerosis,17 and sepsis.18,19Download figureDownload PowerPointFigure. The impact of MPO (myeloperoxidase) on the endothelium. Classically, MPO produces HOCl near the neutrophil-endothelial interface. Apart from the catalytic activity, MPO can also recruit and activate neutrophils. This novel article demonstrates a physical interaction between MPO and heparan sulfate, leading to glycocalyx collapse. After transcytosis into the subendothelial space, MPO can also target extracellular matrix proteins and reduce NO bioavailability.In this issue of ATVB, Manchanda et al20 reveal yet another deleterious role of MPO on the endothelium. Their cell culture and in vivo mouse studies elegantly demonstrate that MPO leads to the collapse of the endothelial glycocalyx. The authors revealed a novel mechanism in which MPO forms a physical interaction with glycocalyx heparan sulfate glycosaminoglycan residues leading to glycocalyx collapse, independent of the classic catalytic function of MPO. The cationic charge of MPO destabilizes the negatively charged endothelial glycocalyx, allowing for neutrophil recruitment and subsequent activation. Furthermore, MPO also stimulated the shedding of syndecan-1, a marker of endothelial glycocalyx breakdown. This is significant because these studies uncover another deleterious role of MPO on the endothelium.Although this report by Manchanda et al20 reveals a novel function of MPO, it also raises multiple questions. The exact mechanism by which MPO binds to heparan sulfate remains to be elucidated. Does MPO have specific binding sites or rather is MPO binding nonspecific for heparan sulfate? Heparan sulfate binds to proteins using a small number of cationic surface amino acids. The authors suggest that the binding is nonspecific because MPO has >70 of these cationic amino acids. Positive control experiments also showed positively charged polylysine binds to the glycocalyx reducing its negative charge. It is also important to note that neutrophil primary granules contain other cationic proteins, and these results do not exclude the possibility of their impact on the endothelial glycocalyx.Overall, it is clear that MPO has many roles in changes in the endothelium. Studies examining the impact of MPO on altering endothelial function traditionally have focused on downstream products and actions of MPO catalytic activity, including tyrosine chlorination,21 HOCl production,22 MMP (matrix metalloproteinase) activation by cysteine oxidation,23 and chlorinated lipid production.19 The current study by Manchanda et al20 provides an important new mechanism for MPO elicited endothelial dysfunction. This is potentially an important and novel paradigm, but as is with all new models, important questions remain to be answered to further elucidate this model. Future studies should establish the role of the noncatalytic function of MPO in glycocalyx alterations in human disease.Sources of FundingThis work was supported (in part) by research funding from the National Institutes of Health R01 GM-115553 to D.A. Ford.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to David A. Ford, PhD, Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 Grand Ave, DRC 325, St. Louis, MO 63104. E-mail david.[email protected]slu.eduReferences1. Agner K. A ferment isolated from leucocytes.Acta Chemica Scandinavica. 1941; 2:1–62.Google Scholar2. Agner K. Crystalline myeloperoxidase.Acta Chemica Scandinavica. 1958; 12:89–94.CrossrefGoogle Scholar3. Hirsch JG, Cohn ZA. Degranulation of polymorphonuclear leucocytes following phagocytosis of microorganisms.J Exp Med. 1960; 112:1005–1014.CrossrefMedlineGoogle Scholar4. Iyer GYN, Islam MF, Quastel JH. Biochemical Aspects of Phagocytosis.Nature. 1961; 192:535.CrossrefGoogle Scholar5. Klebanoff SJ. Myeloperoxidase-halide-hydrogen peroxide antibacterial system.J Bacteriol. 1968; 95:2131–2138.CrossrefMedlineGoogle Scholar6. Klebanoff SJ. Iodination of bacteria: a bactericidal mechanism.J Exp Med. 1967; 126:1063–1078.CrossrefMedlineGoogle Scholar7. Klebanoff SJ. A peroxidase-mediated antimicrobial system in leukocytes.J Clin Invest. 1967; 46:1078A.Google Scholar8. Tiruppathi C, Naqvi T, Wu Y, Vogel SM, Minshall RD, Malik AB. Albumin mediates the transcytosis of myeloperoxidase by means of caveolae in endothelial cells.Proc Natl Acad Sci USA. 2004; 101:7699–7704.CrossrefMedlineGoogle Scholar9. Baldus S, Eiserich JP, Mani A, Castro L, Figueroa M, Chumley P, Ma W, Tousson A, White CR, Bullard DC, Brennan ML, Lusis AJ, Moore KP, Freeman BA. Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration.J Clin Invest. 2001; 108:1759–1770. doi: 10.1172/JCI12617.CrossrefMedlineGoogle Scholar10. Eiserich JP, Baldus S, Brennan ML, Ma W, Zhang C, Tousson A, Castro L, Lusis AJ, Nauseef WM, White CR, Freeman BA. Myeloperoxidase, a leukocyte-derived vascular NO oxidase.Science. 2002; 296:2391–2394. doi: 10.1126/science.1106830.CrossrefMedlineGoogle Scholar11. Baldus S, Heitzer T, Eiserich JP, Lau D, Mollnau H, Ortak M, Petri S, Goldmann B, Duchstein HJ, Berger J, Helmchen U, Freeman BA, Meinertz T, Münzel T. Myeloperoxidase enhances nitric oxide catabolism during myocardial ischemia and reperfusion.Free Radic Biol Med. 2004; 37:902–911. doi: 10.1016/j.freeradbiomed.2004.06.003.CrossrefMedlineGoogle Scholar12. Lau D, Mollnau H, Eiserich JP, Freeman BA, Daiber A, Gehling UM, Brümmer J, Rudolph V, Münzel T, Heitzer T, Meinertz T, Baldus S. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins.Proc Natl Acad Sci USA. 2005; 102:431–436. doi: 10.1073/pnas.0405193102.CrossrefMedlineGoogle Scholar13. Klinke A, Nussbaum C, Kubala L, et al. Myeloperoxidase attracts neutrophils by physical forces.Blood. 2011; 117:1350–1358. doi: 10.1182/blood-2010-05-284513.CrossrefMedlineGoogle Scholar14. Johnson RJ, Couser WG, Chi EY, Adler S, Klebanoff SJ. New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system.J Clin Invest. 1987; 79:1379–1387. doi: 10.1172/JCI112965.CrossrefMedlineGoogle Scholar15. Zhang H, Xu H, Weihrauch D, Jones DW, Jing X, Shi Y, Gourlay D, Oldham KT, Hillery CA, Pritchard KAInhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice.J Lipid Res. 2013; 54:3009–3015. doi: 10.1194/jlr.M038281.CrossrefMedlineGoogle Scholar16. Matthijsen RA, Huugen D, Hoebers NT, de Vries B, Peutz-Kootstra CJ, Aratani Y, Daha MR, Tervaert JW, Buurman WA, Heeringa P. Myeloperoxidase is critically involved in the induction of organ damage after renal ischemia reperfusion.Am J Pathol. 2007; 171:1743–1752. doi: 10.2353/ajpath.2007.070184.CrossrefMedlineGoogle Scholar17. Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, Topol EJ, Sprecher DL, Hazen SL. Association between myeloperoxidase levels and risk of coronary artery disease.JAMA. 2001; 286:2136–2142.CrossrefMedlineGoogle Scholar18. Kothari N, Keshari RS, Bogra J, Kohli M, Abbas H, Malik A, Dikshit M, Barthwal MK. Increased myeloperoxidase enzyme activity in plasma is an indicator of inflammation and onset of sepsis.J Crit Care. 2011; 26:435.e1–435.e7. doi: 10.1016/j.jcrc.2010.09.001.CrossrefGoogle Scholar19. Meyer NJ, Reilly JP, Feng R, Christie JD, Hazen SL, Albert CJ, Franke JD, Hartman CL, McHowat J, Ford DA. Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome.JCI Insight. 2017; 2:e96432.CrossrefMedlineGoogle Scholar20. Manchanda K, Kolarova H, Kerkenpaß C, Mollenhauer M, Vitecek J, Rudolph V, Kubala L, Baldus S, Adam M, Klinke A. MPO (myeloperoxidase) reduces endothelial glycocalyx thickness dependent on its cationic charge.Arterioscler Thromb Vasc Biol. 2018; 38:1859–1867. doi: 10.1161/ATVBAHA.118.311143.Google Scholar21. Hazen SL, Heinecke JW. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima.J Clin Invest. 1997; 99:2075–2081. doi: 10.1172/JCI119379.CrossrefMedlineGoogle Scholar22. Stocker R, Huang A, Jeranian E, Hou JY, Wu TT, Thomas SR, Keaney JFHypochlorous acid impairs endothelium-derived nitric oxide bioactivity through a superoxide-dependent mechanism.Arterioscler Thromb Vasc Biol. 2004; 24:2028–2033. doi: 10.1161/01.ATV.0000143388.20994.fa.LinkGoogle Scholar23. Fu X, Kassim SY, Parks WC, Heinecke JW. Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase.J Biol Chem. 2001; 276:41279–41287. doi: 10.1074/jbc.M106958200.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByMohammadi L, Han D, Xu F, Huang A, Derakhshandeh R, Rao P, Whitlatch A, Cheng J, Keith R, Hamburg N, Ganz P, Hellman J, Schick S and Springer M (2022) Chronic E-Cigarette Use Impairs Endothelial Function on the Physiological and Cellular Levels, Arteriosclerosis, Thrombosis, and Vascular Biology, 42:11, (1333-1350), Online publication date: 1-Nov-2022. Ren R, Xu Z, Wang X, Jiang W and Yu P (2022) Verdiperstat attenuates acute lung injury by modulating MPO/μ-calpain/β-catenin signaling, European Journal of Pharmacology, 10.1016/j.ejphar.2022.174940, 924, (174940), Online publication date: 1-Jun-2022. Yang Y, Liu L, Guo Z, Li L, Shao Y, Song M and Sun B (2021) Investigation and assessment of neutrophil dysfunction early after severe burn injury, Burns, 10.1016/j.burns.2021.02.004, 47:8, (1851-1862), Online publication date: 1-Dec-2021. Ning K, Jiang L, Hu T, Wang X, Liu A, Bao Y and Carrabba N (2020) ATP-Sensitive Potassium Channels Mediate the Cardioprotective Effect of Panax notoginseng Saponins against Myocardial Ischaemia–Reperfusion Injury and Inflammatory Reaction, BioMed Research International, 10.1155/2020/3039184, 2020, (1-12), Online publication date: 20-Oct-2020. Khan M, Singh P, Dohare R, Jha R, Rahmani A, Almatroodi S, Ali S and Syed M (2020) Inhibition of miRNA-34a Promotes M2 Macrophage Polarization and Improves LPS-Induced Lung Injury by Targeting Klf4, Genes, 10.3390/genes11090966, 11:9, (966) Zhang L, Wang X, Cueto R, Effi C, Zhang Y, Tan H, Qin X, Ji Y, Yang X and Wang H (2019) Biochemical basis and metabolic interplay of redox regulation, Redox Biology, 10.1016/j.redox.2019.101284, 26, (101284), Online publication date: 1-Sep-2019. Rababa'h A, Bsoul R, Alkhatatbeh M, Alzoubi K and Khabour O (2019) Waterpipe tobacco smoke distresses cardiovascular biomarkers in mice: alterations in protein expression of metalloproteinases, endothelin and myeloperoxidase, Inhalation Toxicology, 10.1080/08958378.2019.1606366, 31:3, (99-106), Online publication date: 23-Feb-2019. Related articlesMPO (Myeloperoxidase) Reduces Endothelial Glycocalyx Thickness Dependent on Its Cationic ChargeKashish Manchanda, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:1859-1867 August 2018Vol 38, Issue 8 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.118.311427PMID: 30354198 Originally publishedJuly 25, 2018 Keywordsvascular diseaseatherosclerosisglycocalyxEditorialssepsisphagocytosisPDF download Advertisement
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