Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

Huang, Ying; Wu, Zhiping; Riwanto, Meliana; Gao, Shengqiang; Levison, Bruce S.; Gu, Xiaodong; Fu, Xiaoming; Wagner, Matthew A.; Besler, Christian; Gerstenecker, Gary; Zhang, Renliang; Li, Xin-Min; DiDonato, Anthony J.; Gogonea, Valentin; Tang, W.H. Wilson; Smith, Jonathan D.; Plow, Edward F.; Fox, Paul L.; Shih, Diana M.; Lusis, Aldons J.; Fisher, Edward A.; DiDonato, Joseph A.; Landmesser, Ulf; Hazen, Stanley L.

doi:10.1172/jci67478

Cited by 269Paraoxonase enzyme and polymorphismsNeutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stress

Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

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Huang, Ying, Wu, Zhiping, Riwanto, Meliana, Gao, Shengqiang, Levison, Bruce S., Gu, Xiaodong, Fu, Xiaoming, Wagner, Matthew A. +16 more·2013·Journal of Clinical Investigation

DOI 10.1172/jci67478PMC PMC3754253

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Abstract

Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein-associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr71), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other's function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.

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Unlike HDL from healthy subjects, HDL from patients with CHD, kidney disease or diabetes mellitus have no protective vascular effects or may even cause paradoxical harmful effects.
“Unlike HDL from healthy subjects, HDL from patients with CHD, kidney disease or diabetes mellitus have no protective vascular effects or may even cause paradoxical harmful effects [55, 56, 61, 70, 71, 75, 76].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [76]

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Rotational and hinge dynamics of discoidal high density lipoproteins probed by interchain disulfide bond formation
Li, L., Li, S., Jones, M. K., & Segrest, J. P. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2011.10.013 · Cited by 19 · see citing works
Injection of paraoxonase 1 (PON1) to mice stimulates their HDL and macrophage antiatherogenicity
Rosenblat, M., Volkova, N., & Aviram, M. (2011) · BioFactors · doi:10.1002/biof.188 · Cited by 19 · see citing works

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Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel
Borén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., Daemen, M. J., Demer, L. L., Hegele, R. A., Nicholls, S. J., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz962 · Cited by 1,601 · see citing works
“amino acid residues in apoAI by macrophage-derived myeloperoxidase;(282) moreover, oxidative modification also alters the endothelial effects of HDL.(283,284) These observations raise the possibility that a”
BackgroundSelf-citation
Vascular oxidative stress, nitric oxide and atherosclerosis
Li, H., Horke, S., & Förstermann, U. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.09.001 · Cited by 656 · see citing works
“Interestingly, it has been found that while PON1 can diminish MPO-produced ROS, MPO in turn can inactivate PON1, thus resulting in a delicate equilibrium that determines the anti-atherogenic capacity of HDLs [97].”
Background
Impact of Oxidative Stress on the Heart and Vasculature
Münzel, T. F., Camici, G. G., Maack, C., Bonetti, N. R., Fuster, V., & Kovacic, J. C. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.05.035 · Cited by 623 · see citing works
“It inhibits ROS production by myeloperoxidase (MPO), an enzyme secreted by immune cells upon activation and an accepted biomarker in acute coronary syndrome (93), thereby reducing oxidative stress, inflammation, and monocyte attraction.”
Targeting vascular (endothelial) dysfunction
Daiber, A., Steven, S., Weber, A., Shuvaev, V. V., Muzykantov, V. R., Laher, I., Li, H., Lamas, S., & Münzel, T. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13517 · Cited by 501 · see citing works
Inflammation and cardiovascular disease: From mechanisms to therapeutics
Alfaddagh, A., Martin, S. S., Leucker, T. M., Michos, E. D., Blaha, M. J., Lowenstein, C. J., Jones, S. R., & Toth, P. P. (2020) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2020.100130 · Cited by 473 · see citing works
“Abbreviations: AGEs, Advanced glycation end products; FA, free fatty acids; TNF-α chemoattractant protein-1; ROS, reactive oxygen species; SCFA, short-chain fatty aci low-density lipoprotein; HDL, high-density lipoprotein; ApoC III, apolipoprotein C II (Fig.”
BackgroundInfluential
Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting
Soppert, J., Lehrke, M., Marx, N., Jankowski, J., & Noels, H. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.019 · Cited by 419 · see citing works
HDL cholesterol: reappraisal of its clinical relevance
März, W., Kleber, M. E., Scharnagl, H., Speer, T., Zewinger, S., Ritsch, A., Parhofer, K. G., von Eckardstein, A., Landmesser, U., & Laufs, U. (2017) · Clinical Research in Cardiology · doi:10.1007/s00392-017-1106-1 · Cited by 275 · see citing works
“Unlike HDL from healthy subjects, HDL from patients with CHD, kidney disease or diabetes mellitus have no protective vascular effects or may even cause paradoxical harmful effects [55, 56, 61, 70, 71, 75, 76].”
BackgroundSelf-citation
Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit
Brites, F. D., Martín, M., Guillas, I., & Kontush, A. (2017) · BBA Clinical · doi:10.1016/j.bbacli.2017.07.002 · Cited by 265 · see citing works
Redox Regulation of Inflammation: Old Elements, a New Story
Lei, Y., Wang, K., Deng, L., Chen, Y., Nice, E. C., & Huang, C. (2014) · Medicinal Research Reviews · doi:10.1002/med.21330 · Cited by 208 · see citing works
OxInflammation: From Subclinical Condition to Pathological Biomarker
Valacchi, G., Virgili, F., Cervellati, C., & Pecorelli, A. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00858 · Cited by 206 · see citing works
High density lipoproteins: Measurement techniques and potential biomarkers of cardiovascular risk
Hafiane, A., & Genest, J. J. (2015) · BBA Clinical · doi:10.1016/j.bbacli.2015.01.005 · Cited by 195 · see citing works
Antioxidant properties of HDL
Soran, H., Schofield, J. D., & Durrington, P. N. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00222 · Cited by 188 · see citing works
“It has recently been proposed that MPO and PON1 form a ternary complex with HDL, where the opposing activities of MPO and PON1 determine its oxidation state and whether HDL is pro- or anti-inflammatory/atherogenic (Huang et al., 2013).”
Background
Role of myeloperoxidase and oxidant formation in the extracellular environment in inflammation-induced tissue damage
Hawkins, C. L., & Davies, M. J. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.007 · Cited by 181 · see citing works
The impact of reactive oxygen species in the development of cardiometabolic disorders: a review
Akhigbe, R. E., & Ajayi, A. F. (2021) · Lipids in Health and Disease · doi:10.1186/s12944-021-01435-7 · Cited by 154 · see citing works
Paraoxonase and atherosclerosis-related cardiovascular diseases
Chistiakov, D. A., Melnichenko, A. А., Orekhov, A. N., & Bobryshev, Y. V. (2016) · Biochimie · doi:10.1016/j.biochi.2016.10.010 · Cited by 156 · see citing works
High-Density Lipoprotein Function and Dysfunction in Health and Disease
Chiesa, S. T., & Charakida, M. (2019) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-018-06846-w · Cited by 150 · see citing works
HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy
Linton, M. F., Yancey, P. G., Tao, H., & Davies, S. S. (2023) · Circulation Research · doi:10.1161/circresaha.123.321563 · Cited by 155 · see citing works
A Comparison of the Mouse and Human Lipoproteome: Suitability of the Mouse Model for Studies of Human Lipoproteins
Gordon, S. M., Li, H., Zhu, X., SHAH, A. S., Lu, L. J., & Davidson, W. S. (2015) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b00213 · Cited by 143 · see citing works
Inflammation in Neurological Disorders: The Thin Boundary Between Brain and Periphery
Cervellati, C., Trentini, A., Pecorelli, A., & Valacchi, G. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8076 · Cited by 138 · see citing works
“A similar attitude to translate an inﬂammatory signal into oxidant production is possessed by Myeloperoxidase, a heme-peroxidase mainly produced by granulocytes and monocytes with an important role as a ﬁrst-line defense against microbial infections (78).”
Inference and quantification of peptidoforms in large sample cohorts by SWATH-MS
Rosenberger, G., Liu, Y., Röst, H. L., Ludwig, C., Buil, A., Bensimon, A., Soste, M., Spector, T. D., Dermitzakis, E. T., Collins, B. C., et al. (2017) · Nature Biotechnology · doi:10.1038/nbt.3908 · Cited by 121 · see citing works
Biological Consequences of Dysfunctional HDL
Pirillo, A., Catapano, A. L., & Norata, G. D. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180530110543 · Cited by 119 · see citing works
Dysfunctional HDL in diabetes mellitus and its role in the pathogenesis of cardiovascular disease
Srivastava, R. A. K. (2017) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-017-3165-z · Cited by 111 · see citing works
“Among these associated proteins, PON1 appears to be the most important player in conferring antioxidant property to HDL particles to protect LDL from undergoing oxidation [54].”
Disordered haematopoiesis and athero-thrombosis
Murphy, A. J., & Tall, A. R. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehv718 · Cited by 109 · see citing works
The Role of Lipids and Lipoproteins in Atherosclerosis
Linton, M. F., Yancey, P. G., Davies, S. S., Jerome, W. G., Linton, E. F., Song, W., Doran, A. C., & Vickers, K. C. (2015) · Europe PMC (PubMed Central) · Cited by 108 · see citing works
High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease
Kratzer, A., Giral, H., & Landmesser, U. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu139 · Cited by 109 · see citing works
“Interestingly, HDL serves as a scaffold upon which MPO and PON1 interact during inflammation, generating a ternary complex during acute inflammation that shows reciprocal regulation of enzymatic activities where PON1 partially inhibits MPO oxidative activity while MPO can inactivate PON1.(136) MPO oxidizes Tyr71 of PO…”
BackgroundSelf-citation
Paraoxonase 1 in neurological disorders
Menini, T., & Gugliucci, A. (2013) · Redox Report · doi:10.1179/1351000213y.0000000071 · Cited by 103 · see citing works
The Structure and Function of Paraoxonase-1 and Its Comparison to Paraoxonase-2 and -3
Taler‐Verčič, A., Goličnik, M., & Bavec, A. (2020) · Molecules · doi:10.3390/molecules25245980 · Cited by 97 · see citing works
Paraoxonase 1 and HDL maturation
Gugliucci, A., & Menini, T. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.09.016 · Cited by 95 · see citing works
“4, MPO, PON1, and HDL bind to one another, establishing a ternary complex, where PON1 moderately hinders MPO activity, while MPO inactivates PON1 [84].”
BackgroundInfluential
Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy
Annema, W., & von Eckardstein, A. (2016) · Translational Research · doi:10.1016/j.trsl.2016.02.008 · Cited by 94 · see citing works
HDL and Reverse Remnant-Cholesterol Transport (RRT): Relevance to Cardiovascular Disease
Kontush, A. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.07.005 · Cited by 90 · see citing works
“In addition, apoA-I forms complexes with proteins displaying prominent anti-atherosclerotic and anti-11 inflammatory properties, such as paraoxonase 1, further enhancing atheroprotection [59].”
Effects of bioactive lipids and lipoproteins on bone
Tintut, Y., & Demer, L. L. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.10.001 · Cited by 90 · see citing works
AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE−/− mice
Ma, A., Wang, J., Liu, Y., An, Y., & Zhu, H. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m073270 · Cited by 89 · see citing works
“Conversely, PON1 has antioxidant properties and mediates some of the atheroprotective functions attributed to HDL (7, 33).”
Background
The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions
Robert, J., Osto, E., & von Eckardstein, A. (2021) · Cells · doi:10.3390/cells10051041 · Cited by 88 · see citing works
Importance of paraoxonase 1 (PON1) as an antioxidant and antiatherogenic enzyme in the cardiovascular complications of type 2 diabetes: Genotypic and phenotypic evaluation
Shokri, Y., Variji, A., Nosrati, M., Khonakdar-Tarsi, A., Kianmehr, A., Kashi, Z., Bahar, A., Bagheri, A., & Mahrooz, A. (2020) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2020.108067 · Cited by 87 · see citing works
Paraoxonase 1 and atherosclerosis‐related diseases
Kotur‐Stevuljević, J., Vekić, J., Stefanović, A., Zeljković, A., Ninić, A., Ivanišević, J., Miljković, M., Sopić, M., Munjas, J., Mihajlović, M., et al. (2019) · BioFactors · doi:10.1002/biof.1549 · Cited by 86 · see citing works
Endocan Levels and Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus
İçli, A., Cüre, E., Cüre, M. C., Uslu, A. U., Balta, Ş., Mikhailidis, D. P., Öztürk, C., Arslan, Ş., Sakız, D., Sahin, M., et al. (2015) · Angiology · doi:10.1177/0003319715616240 · Cited by 86 · see citing works
“However, HDL is sensitive to modification by various oxidants.(41) Therefore, the antiatherosclerotic effect of high HDL-C levels may be impaired in patients with SLE.”
Background
The role of high-density lipoprotein cholesterol, apolipoprotein A and paraoxonase-1 in the pathophysiology of neuroprogressive disorders
Morris, G., Puri, B. K., Bortolasci, C. C., Carvalho, A., Berk, M., Walder, K., Moreira, E. G., & Maes, M. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.02.037 · Cited by 84 · see citing works
Subfractions and Subpopulations of HDL: An Update
Rizzo, M., Otvos, J. D., Nikolić, D., Montalto, G., Toth, P. P., & Banach, M. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666140414103455 · Cited by 84 · see citing works
“A recent in vivo study suggests that during inflammation myeloperoxidase (MPO) and PON1 interact, PON1 moderately inhibits MPO activity, and MPO stimulates site-specific oxidative modification and deterioration of PON1 and APOA1 activity [98].”
Background
Myeloperoxidase: A versatile mediator of endothelial dysfunction and therapeutic target during cardiovascular disease
Maiocchi, S. L., Ku, J., Thai, T., Chan, E., Rees, M. D., & Thomas, S. R. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107711 · Cited by 75 · see citing works
Generalized Anxiety Disorder (GAD) and Comorbid Major Depression with GAD Are Characterized by Enhanced Nitro-oxidative Stress, Increased Lipid Peroxidation, and Lowered Lipid-Associated Antioxidant Defenses
Maes, M. H. J., Bonifácio, K. L., Morelli, N. R., Vargas, H. O., Moreira, E. G., Stoyanov, D., Barbosa, D. S., Carvalho, A. F., & Nunes, S. O. V. (2018) · Neurotoxicity Research · doi:10.1007/s12640-018-9906-2 · Cited by 76 · see citing works
Paraoxonase 1 and atherosclerosis
Durrington, P. N., Bashir, B., & Soran, H. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1065967 · Cited by 80 · see citing works
Oxidative stress and antioxidant defenses in mild cognitive impairment: A systematic review and meta-analysis
Nantachai, G., Vasupanrajit, A., Tunvirachaisakul, C., Solmi, M., & Maes, M. H. J. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101639 · Cited by 71 · see citing works
The other myeloperoxidase: Emerging functions
Vanhamme, L., Boudjeltia, K. Z., Antwerpen, P. V., & Delporte, C. (2018) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2018.03.037 · Cited by 70 · see citing works
Antioxidant and Anti-Inflammatory Effects of Bioactive Compounds in Atherosclerosis
Roşian, Ş. H., Boarescu, I., & Boarescu, P.-M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031379 · Cited by 69 · see citing works
“For example, Huang et al. identified that myeloperoxidase (MPO) binds to HDL and is mechanistically linked to oxidant stress and atherosclerosis [33].”
HDL function is impaired in acute myocardial infarction independent of plasma HDL cholesterol levels
Annema, W., Willemsen, H. M., de Boer, J. F., Dikkers, A., van der Giet, M., Nieuwland, W., Kobold, A. C. M., van Pelt, L. J., Slart, R. H. J. A., van der Horst, I. C. C., et al. (2016) · Journal of clinical lipidology · doi:10.1016/j.jacl.2016.08.003 · Cited by 66 · see citing works
Dysfunctional high-density lipoproteins have distinct composition, diminished anti-inflammatory potential and discriminate acute coronary syndrome from stable coronary artery disease patients
Carnuta, M. G., Stancu, C. S., Toma, L., Sanda, G. M., Niculescu, L. S., Deleanu, M., Popescu, A. C., Popescu, M. R., Vlad, A., Dimulescu, D. R., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-07821-5 · Cited by 66 · see citing works
Improvement of High‐Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial
Charles‐Schoeman, C., Lee, Y. Y., Shahbazian, A., Wang, X., Elashoff, D. A., Curtis, J. R., Navarro-Millán, I. Y., Yang, S., Chen, L., Cofield, S. S., et al. (2016) · Arthritis & Rheumatology · doi:10.1002/art.39833 · Cited by 65 · see citing works
“This process occurs in part via prooxidant enzymes such as MPO, and promotes the development of a dysfunctional, even “prooxidant” particle (33) (Figure 1).”
Background
Decreased arylesterase activity of paraoxonase-1 (PON-1) might be a common denominator of neuroinflammatory and neurodegenerative diseases
Castellazzi, M., Trentini, A., Romani, A., Valacchi, G., Bellini, T., Bonaccorsi, G., Fainardi, E., Cavicchio, C., Passaro, A., Zuliani, G., et al. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.06.008 · Cited by 63 · see citing works
Functional and proteomic alterations of plasma high density lipoproteins in type 1 diabetes mellitus
Manjunatha, S., Distelmaier, K., Dasari, S., Carter, R. E., Kudva, Y. C., & Nair, K. S. (2016) · Metabolism · doi:10.1016/j.metabol.2016.06.008 · Cited by 62 · see citing works
HDL: Fact, fiction, or function? HDL cholesterol and cardiovascular risk
Allard‐Ratick, M., Kindya, B., Khambhati, J., Engels, M. C., Sandesara, P. B., Rosenson, R. S., & Sperling, L. S. (2019) · European Journal of Preventive Cardiology · doi:10.1177/2047487319848214 · Cited by 62 · see citing works
High-density lipoprotein metabolism, composition, function, and deficiency
Schaefer, E. J., Anthanont, P., & Asztalos, B. F. (2014) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000074 · Cited by 60 · see citing works
Inflammation, Infection, Cancer and All That…The Role of Paraoxonases
Devarajan, A., Shih, D. M., & Reddy, S. T. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-07320-0_5 · Cited by 59 · see citing works
“Recent detailed biochemical studies have further elucidated how PON1 exerts its antiinflammatory and anti-oxidative functions [23, 33].”
BackgroundSelf-citation
Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers
Riwanto, M., Rohrer, L., von Eckardstein, A., & Landmesser, U. (2014) · Handbook of experimental pharmacology · doi:10.1007/978-3-319-09665-0_10 · Cited by 59 · see citing works
“Recently, we have shown that MPO and PON1 interact and reciprocally modulate each other’s function in vivo, i.e., PON1 partially inhibits MPO activity, while MPO oxidizes and inactivates PON1 (Huang et al. 2013).”
BackgroundInfluentialSelf-citation
HDL Proteome and Alzheimer’s Disease: Evidence of a Link
Marsillach, J., Adorni, M. P., Zimetti, F., Papotti, B., Zuliani, G., & Cervellati, C. (2020) · Antioxidants · doi:10.3390/antiox9121224 · Cited by 57 · see citing works
High-Density Lipoprotein Regulation of Mitochondrial Function
White, C. R., Datta, G., & Giordano, S. S. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-55330-6_22 · Cited by 58 · see citing works
Why Should Psychiatrists and Neuroscientists Worry about Paraoxonase 1?
Moreira, E. G., Boll, K. M., Correia, D. G., Soares, J. F., Rigobello, C., & Maes, M. H. J. (2018) · Current Neuropharmacology · doi:10.2174/1570159x17666181227164947 · Cited by 57 · see citing works
Functionality of HDL: Antioxidation and Detoxifying Effects
Karlsson, H., Kontush, A., & James, R. W. (2015) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-319-09665-0_5 · Cited by 55 · see citing works
Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis
O'Neill, F., Charakida, M., Topham, E., McLoughlin, E., Patel, N. P., Sutill, E., Kay, C. W. M., D’Aiuto, F., Landmesser, U., Taylor, P. C., et al. (2016) · Heart · doi:10.1136/heartjnl-2015-308953 · Cited by 55 · see citing works
Self-citation
Atherogenesis: hyperhomocysteinemia interactions with LDL, macrophage function, paraoxonase 1, and exercise
Chernyavskiy, I., Veeranki, S., Sen, U., & Tyagi, S. C. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13009 · Cited by 55 · see citing works
Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: a Nomothetic Network Psychiatry Approach
Maes, M. H. J., Sirivichayakul, S., Matsumoto, A. K., Michelin, A. P., Semeão, L. D. O., Pedrão, J. V. D. L., Moreira, E. G., Barbosa, D. S., Carvalho, A. F., Solmi, M., et al. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02047-5 · Cited by 50 · see citing works
High-Density Lipoprotein Modifications: A Pathological Consequence or Cause of Disease Progression?
Márquez, A. B., Nazir, S., & van der Vorst, E. P. C. (2020) · Biomedicines · doi:10.3390/biomedicines8120549 · Cited by 53 · see citing works
Myeloperoxidase: a potential therapeutic target for coronary artery disease
Chaikijurajai, T., & Tang, W. H. W. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1762177 · Cited by 53 · see citing works
Self-citation
Connection between the Altered HDL Antioxidant and Anti-Inflammatory Properties and the Risk to Develop Alzheimer’s Disease: A Narrative Review
Zimetti, F., Adorni, M. P., Marsillach, J., Marchi, C., Trentini, A., Valacchi, G., & Cervellati, C. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6695796 · Cited by 49 · see citing works
“The oxidative challenge of this leukocyte-derived enzyme is facilitated by its physical association with ApoA1 and HDL particles [14].”
Background
Effect of yerba mate and green tea on paraoxonase and leptin levels in patients affected by overweight or obesity and dyslipidemia: a randomized clinical trial
Balsan, G. A., Pellanda, L. C., Sausen, G., Galarraga, T., Zaffari, D., Pontin, B., & Portal, V. L. (2019) · Nutrition Journal · doi:10.1186/s12937-018-0426-y · Cited by 53 · see citing works
“The LDL-c was calculated by the Friedwald equation and was not the only lipid parameter considered because our interventions could cause changes in both HDL-c and triglycerides.”
BackgroundInfluential
Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics
Salazar, J. J., Olivar, L. C., Ramos, E., Chávez-Castillo, M., Rojas, J., & Bermúdez, V. (2015) · Cholesterol · doi:10.1155/2015/296417 · Cited by 48 · see citing works
“In spite of these findings, there is conflictive evidence regarding the “protective” role of HDL-C in cardiovascular”
Result
The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure
Werbner, B., Tavakoli‐Rouzbehani, O. M., Fatahian, A. N., & Boudina, S. (2023) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2022.42 · Cited by 44 · see citing works
High-density lipoprotein and inflammation in cardiovascular disease
Connelly, M. A., SHALAUROVA, I. Y., & Otvos, J. D. (2016) · Translational research · doi:10.1016/j.trsl.2016.01.006 · Cited by 46 · see citing works
Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: A qualitative relationship?
Gómez, M. C. G. (2014) · World Journal of Orthopedics · doi:10.5312/wjo.v5.i3.304 · Cited by 45 · see citing works
Dysfunctional HDL as a Therapeutic Target for Atherosclerosis Prevention
Ossoli, A., Pavanello, C., Giorgio, E., Calabresi, L., & Gomaraschi, M. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180316115726 · Cited by 45 · see citing works
Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways
Curaj, A., Vanholder, R. C., Loscalzo, J., Quach, K., Wu, Z., Jankowski, V., & Jankowski, J. (2024) · Circulation Research · doi:10.1161/circresaha.123.324001 · Cited by 46 · see citing works
“162 Normal healing after myocardial ischemia or infarction is essential for cardiac function.”
BackgroundSelf-citation
Modification by isolevuglandins, highly reactive γ-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function
Zhang, L., Yermalitsky, V. N., Huang, J., Pleasent, T., Borja, M. S., Oda, M. N., Jerome, W. G., Yancey, P. G., Linton, M. F., & Davies, S. S. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001099 · Cited by 44 · see citing works
“Because MPO complexes with apoA-I on HDL (21), these impairments are probably due to oxidative targeting of apoA-I (22).”
Background
Apolipoprotein A-1 mimetic peptide 4F promotes endothelial repairing and compromises reendothelialization impaired by oxidized HDL through SR-B1
He, D., Zhao, M., Wu, C., Zhang, W., Niu, C., Yu, B., Jin, J., Ji, L., Willard, B. B., Mathew, A. V., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.11.027 · Cited by 43 · see citing works
The combined utility of myeloperoxidase (MPO) and paraoxonase 1 (PON1) as two important HDL-associated enzymes in coronary artery disease: Which has a stronger predictive role?
Variji, A., Shokri, Y., Fallahpour, S., Zargari, M., Bagheri, B., Abediankenari, S., Alizadeh, A., & Mahrooz, A. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.11.004 · Cited by 43 · see citing works
Myeloperoxidase level and inflammatory markers and lipid and lipoprotein parameters in stable coronary artery disease
Kimak, E., Zieba, B. J., Duma, D., & Solski, J. (2018) · Lipids in Health and Disease · doi:10.1186/s12944-018-0718-4 · Cited by 42 · see citing works
“These results suggest that a high MPO and TG level and disorder of apoB/apoAI and TG/HDL-C ratios together with high inflammatory markers decreased HDL-C and apoAI concentration and disturbed the composition of HDL-C and apoAI in HDL, and the anti-inflammatory and anti-oxidative functions of HDL particles [7, 13].”
The Difference Between High Density Lipoprotein Subfractions and Subspecies: an Evolving Model in Cardiovascular Disease and Diabetes
Davidson, W. S., Cooke, A. L., Swertfeger, D. K., & SHAH, A. S. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00925-4 · Cited by 41 · see citing works
Association of the serum myeloperoxidase/high-density lipoprotein particle ratio and incident cardiovascular events in a multi-ethnic population: Observations from the Dallas Heart Study
Khine, H., Teiber, J. F., Haley, R. W., Khera, A., Ayers, C. R., & Rohatgi, A. K. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.06.007 · Cited by 41 · see citing works
High-Density Lipoprotein Subfractions and Their Oxidized Subfraction Particles in Patients with Chronic Kidney Disease
Honda, H., Hirano, T., Ueda, M., Kojima, S., Mashiba, S., Hayase, Y., Michihata, T., & Shibata, T. (2015) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.30015 · Cited by 41 · see citing works
Structural Insights into High Density Lipoprotein: Old Models and New Facts
Gogonea, V. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00318 · Cited by 40 · see citing works
Self-citation
Evaluating the link between Paraoxonase-1 levels and Alzheimer's disease development
Cervellati, C., Valacchi, G., Tisato, V., Zuliani, G., & Marsillach, J. (2019) · Minerva Medica · doi:10.23736/s0026-4806.18.05875-5 · Cited by 40 · see citing works
Angiogenic and Antiangiogenic mechanisms of high density lipoprotein from healthy subjects and coronary artery diseases patients
Li, H.-M., Mo, Z.-W., Peng, Y.-M., Li, Y., Dai, W.-P., Yuan, H., Chang, F.-J., Wang, T., Wang, M., Hu, K.-H., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101642 · Cited by 39 · see citing works
Self-citation
Catalytic Stimulation by Restrained Active-Site Floppiness—The Case of High Density Lipoprotein-Bound Serum Paraoxonase-1
Ben-David, M., Sussman, J. L., Maxwell, C. I., Szeler, K., Kamerlin, S. C. L., & Tawfik, D. S. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.01.013 · Cited by 38 · see citing works
“Indeed, our results suggest that restraining unnecessary conformational freedom via second- and third-shell interactions comprises a general feature of enzyme catalysis.”
Background
Imbalance between Endothelial Damage and Repair: A Gateway to Cardiovascular Disease in Systemic Lupus Erythematosus
Mak, A., & Kow, N. Y. (2014) · BioMed Research International · doi:10.1155/2014/178721 · Cited by 38 · see citing works
Disability in multiple sclerosis is associated with age and inflammatory, metabolic and oxidative/nitrosative stress biomarkers: results of multivariate and machine learning procedures
Flauzino, T., Simão, A. N. C., Pereira, W. L. D. C. J., Alfieri, D. F., Oliveira, S. R., Kallaur, A. P., Lozovoy, M. A. B., Kaimen-Maciel, D. R., Maes, M. H. J., & Reiche, E. M. V. (2019) · Metabolic Brain Disease · doi:10.1007/s11011-019-00456-7 · Cited by 39 · see citing works
How HDL protects LDL against atherogenic modification
Soran, H., Schofield, J. D., Liu, Y., & Durrington, P. N. (2015) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000194 · Cited by 38 · see citing works
Implications of reverse cholesterol transport: Recent studies
Levinson, S. S., & Wagner, S. G. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.10.018 · Cited by 36 · see citing works
Paraoxonase-1 activities in individuals with different HDL circulating levels: Implication in reverse cholesterol transport and early vascular damage
Cervellati, C., Vigna, G. B., Trentini, A., Sanz, J. M., Zimetti, F., Nora, E. D., Morieri, M. L., Zuliani, G., & Passaro, A. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.04.218 · Cited by 36 · see citing works
Apolipoprotein A1, the neglected relative of Apolipoprotein E and its potential role in Alzheimer’s disease
Endres, K. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.310669 · Cited by 36 · see citing works
“Significantly, ApoA1 is found, for example, in direct contact with myeloperoxidase (Huang et al., 2013), an enzyme that plays a crucial role in antimicrobial defense starting from neutrophil granulocytes.”
Background
Plasma oxidation status and antioxidant capacity in psoriatic children
Bacchetti, T., Simonetti, O., Ricotti, F., Offidani, A., & Ferretti, G. (2019) · Archives of Dermatological Research · doi:10.1007/s00403-019-01976-z · Cited by 34 · see citing works
Good Cholesterol Gone Bad? HDL and COVID-19
Kluck, G. E. G., Yoo, J., Sakarya, E. H., & Trigatti, B. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910182 · Cited by 34 · see citing works
High-Density Lipoprotein-Associated Paraoxonase-1 Activity for Prediction of Adverse Outcomes in Outpatients with Chronic Heart Failure
Hammadah, M., Kalogeropoulos, A. P., Georgiopoulou, V. V., Weber, M. E., Wu, Y., Hazen, S. L., Butler, J., & Tang, W. H. W. (2017) · European Journal of Heart Failure · doi:10.1002/ejhf.777 · Cited by 33 · see citing works
“( 6) PON-1 catalytic activity within crude serum mixtures has traditionally been measured by quantifying enzymatic hydrolysis rates of 2 known in vitro substrates, with functional activities named paraoxonase (hydrolyzes organophosphates, like paraoxon) and arylesterase (hydrolyzes aromatic esters,…”
MethodSelf-citation
Paraoxonase, arylesterase and lactonase activities of paraoxonase-1 (PON1) in obese and severely obese women
Cervellati, C., Bonaccorsi, G., Trentini, A., Valacchi, G., Sanz, J. M., Squerzanti, M., Spagnolo, M., Massari, L., Crivellari, I., Greco, P., et al. (2017) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365513.2017.1405274 · Cited by 34 · see citing works
“Furthermore, other studies consistently showed that HDLs of subjects with CVD have lower PON1 activity compared to those of healthy subjects [10,21,22].”
Result
Dysfunctional High-density Lipoprotein: The Role of Myeloperoxidase and Paraoxonase-1
Bacchetti, T., Ferretti, G., Carbone, F., Ministrini, S., Montecucco, F., Jamialahmadi, T., & Sahebkar, A. (2020) · Current Medicinal Chemistry · doi:10.2174/0929867327999200716112353 · Cited by 33 · see citing works
Plasminogen Activator Inhibitor-1 Level Correlates with Lipoprotein Subfractions in Obese Nondiabetic Subjects
Somodi, S., Seres, I., Lőrincz, H., Harangi, M., Fülöp, P., & Paragh, G. (2018) · International Journal of Endocrinology · doi:10.1155/2018/9596054 · Cited by 33 · see citing works
“Recent data indicate that MPO, PON1, and HDL may bind and inhibit each other, forming a ternary complex [22].”
Background
Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction
Gu, X., Huang, Y. R., Levison, B. S., Gerstenecker, G. S., DiDonato, A. J., Hazen, L. B., Lee, J., Gogonea, V., DiDonato, J. A., & Hazen, S. L. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.678334 · Cited by 31 · see citing works
Self-citation
Expression of Serum Exosomal miRNA 122 and Lipoprotein Levels in Dogs Naturally Infected by Leishmania infantum: A Preliminary Study
Loria, A. D., Dattilo, V., Santoro, D., Guccione, J., Luca, A. D., Ciaramella, P., Pirozzi, M., & Iaccino, E. (2020) · Animals · doi:10.3390/ani10010100 · Cited by 32 · see citing works
Lipids at the Nexus between Cerebrovascular Disease and Vascular Dementia: The Impact of HDL-Cholesterol and Ceramides
Sergi, D., Zauli, E., Tisato, V., Secchiero, P., Zauli, G., & Cervellati, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054403 · Cited by 32 · see citing works
“In particular, myeloperoxidase appears to mediate the oxidation of specific residues of ApoA1 which are implicated in triggering cholesterol efflux mechanisms [40].”
Background
Paraoxonase 2 prevents the development of heart failure
Li, W., Kennedy, D. J., Shao, Z., Wang, X., Kamdar, A. K., Weber, M. E., Mislick, K., Kiefer, K., Morales, R., Agatisa-Boyle, B., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.04.583 · Cited by 31 · see citing works
Self-citation
High‐density lipoprotein in diabetes: Structural and functional relevance
Lui, D. T. W., & Tan, K. C. B. (2024) · Journal of Diabetes Investigation · doi:10.1111/jdi.14172 · Cited by 30 · see citing works
“The presence of MPO renders the HDL subspecies dysfunctional, as MPO is a source of reactive oxygen species and impairs PON1 and apoA-I function 32 .”
Background
Assessment of HDL Cholesterol Removal Capacity: Toward Clinical Application
Toh, R. (2018) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17028 · Cited by 30 · see citing works
Defects in High Density Lipoprotein metabolism and hepatic steatosis in mice with liver-specific ablation of Hepatocyte Nuclear Factor 4A
Thymiakou, E., Othman, A., Hornemann, T., & Kardassis, D. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154307 · Cited by 30 · see citing works

Dysfunctional High-density Lipoprotein: The Role of Myeloperoxidase and Paraoxonase-1
Bacchetti, T., Ferretti, G., Carbone, F., Ministrini, S., Montecucco, F., Jamialahmadi, T., & Sahebkar, A. (2020) · Current Medicinal Chemistry · doi:10.2174/0929867327999200716112353 · Cited by 33 · see citing works
Myeloperoxidase-induced modification of HDL by isolevuglandins inhibits paraoxonase-1 activity
Aggarwal, G., Zhang, L., Yermalitsky, V. N., Dikalov, S., Voinov, M. A., Amarnath, V., Kon, V., Linton, M. F., Vickers, K. C., & Davies, S. S. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101019 · Cited by 22 · see citing works
Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity
Huang, J., Yancey, P. G., Tao, H., Borja, M. S., Smith, L. E., Kon, V., Davies, S. S., & Linton, M. F. (2020) · Nutrients · doi:10.3390/nu12071937 · Cited by 25 · see citing works
Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle
Undurti, A., Huang, Y. R., Lupica, J. A., Smith, J. D., DiDonato, J. A., & Hazen, S. L. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.047605 · Cited by 263 · see citing works
Self-citation
Noncatalytic Functions Are Required for MPO and PON1 in Modulating the Involvement of Monocytes and Endothelial Cells in Atherosclerosis
Li, Y., Liu, Y., & Cheng, Y. (2026) · Biochemistry Research International · doi:10.1155/bri/8149388

Authors: Huang, Y., Wu, Z., Riwanto, M., Gao, S., Levison, B. S., Gu, X., Fu, X., Wagner, M. A., Besler, C., Gerstenecker, G., Zhang, R., Li, X.-M., DiDonato, A. J., Gogonea, V., Tang, W. H. W., Smith, J. D., Plow, E. F., Fox, P. L., Shih, D. M., Lusis, A. J., Fisher, E. A., DiDonato, J. A., Landmesser, U., & Hazen, S. L.
Affiliations: Cleveland Clinic (US)
University of Zurich (CH)
Cleveland State University (US)
St. Jude Children's Research Hospital (US)
University of California, Los Angeles (US)
New York University (US)
Corresponding author: Hazen, Stanley L.
ORCID: Huang, Ying
Wu, Zhiping
Gao, Shengqiang
Levison, Bruce S.
Gu, Xiaodong
Fu, Xiaoming
Wagner, Matthew A.
Besler, Christian
Zhang, Renliang
Gogonea, Valentin
Tang, W.H. Wilson
Smith, Jonathan D.
Plow, Edward F.
Fox, Paul L.
Shih, Diana M.
Lusis, Aldons J.
Fisher, Edward A.
DiDonato, Joseph A.
Landmesser, Ulf
Hazen, Stanley L.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2013-08-01
Volume: 123
Issue: 9
Pages: 3815-3828
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci67478
PMC: PMC3754253
OpenAlex: W2170466777
Cited by: 269
References: 71
Citations by year: 2026: 11 · 2025: 16 · 2024: 12 · 2023: 18 · 2022: 15 · 2021: 24 · 2020: 32 · 2019: 20 · 2018: 25 · 2017: 22 · 2016: 27 · 2015: 22 · 2014: 22 · 2013: 3
FWCI: 16.31
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich)
Funders: Abbott Laboratories
National Research Foundation
Fondation Leducq
National Institutes of Health (UL1TR000439, HL030568)
National Heart, Lung, and Blood Institute (R01HL017964, R01HL094322, P01HL030568, R01HL103931, R01 HL17964, P01HL076491, P01HL098055)
National Center for Advancing Translational Sciences
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: myeloperoxidase, paraoxonase 1, HDL cholesterol, ternary protein complex, apolipoprotein A-I, protein oxidation, chlorotyrosine, acute coronary syndrome, inflammation, atherosclerosis, oxidative stress, antioxidant defense, protein-protein interaction, atheroprotection
MeSH terms: Amino Acid Sequence, Animals, Cell Line, Enzyme Stability, Humans, Lipoproteins, HDL, Mice, Inbred C57BL, Peroxidase, Oxidation-Reduction, Protein Binding, Case-Control Studies, Protein Structure, Secondary, Mice, Knockout, Deuterium Exchange Measurement, Aryldialkylphosphatase, Mice, Protein Interaction Domains and Motifs, Plaque, Atherosclerotic

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Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

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