Role Of Myeloperoxidase Research Articles

Role of Myeloperoxidase, Oxidative Stress, and Inflammation in Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a lung complication of premature births. The leading causes of BPD are oxidative stress (OS) from oxygen treatment, infection or inflammation, and mechanical ventilation. OS activates alveolar myeloid cells with subsequent myeloperoxidase (MPO)-mediated OS. Premature human neonates lack sufficient antioxidative capacity and are susceptible to OS. Unopposed OS elicits inflammation, endoplasmic reticulum (ER) stress, and cellular senescence, culminating in a BPD phenotype. Poor nutrition, patent ductus arteriosus, and infection further aggravate OS. BPD survivors frequently suffer from reactive airway disease, neurodevelopmental deficits, and inadequate exercise performance and are prone to developing early-onset chronic obstructive pulmonary disease. Rats and mice are commonly used to study BPD, as they are born at the saccular stage, comparable to human neonates at 22-36 weeks of gestation. The alveolar stage in rats and mice starts at the postnatal age of 5 days. Because of their well-established antioxidative capacities, a higher oxygen concentration (hyperoxia, HOX) is required to elicit OS lung damage in rats and mice. Neutrophil infiltration and ER stress occur shortly after HOX, while cellular senescence is seen later. Studies have shown that MPO plays a critical role in the process. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), a reversible MPO inhibitor, attenuates BPD effectively. In contrast, the irreversible MPO inhibitor-AZD4831-failed to provide similar efficacy. Interestingly, KYC cannot offer its effectiveness without the existence of MPO. We review the mechanisms by which this anti-MPO agent attenuates BPD.

The role of myeloperoxidase as a biomarker in atherosclerotic cardiovascular disease

Myeloperoxidase (MPO), a heme-containing protein integral to the innate immune system, plays a pivotal role in both bactericidal activity and inflammation regulation. In this comprehensive review, we aim to delve into the extensive literature on MPO’s involvement in cardiovascular disease. Through exhaustive searches of reputable databases such as PubMed, Scopus, and Web of Science, we conducted a thorough analysis to elucidate MPO’s potential as a predictor for cardiovascular disease risk. Evidence suggests that MPO serves as a valuable biomarker, particularly in identifying vulnerable lesions predisposed to rupture,leading to myocardial infarction, especially in the context of acute coronary syndrome. Its early release in response to symptom onset positions MPO as a promising tool for triaging chest pain patients in emergency departments, offering advantages over conventional markers like cardiac troponins. Moreover, studies have demonstrated a correlation between elevated MPO levels and higher mortality rates in patients with acute coronary syndrome, both in short- and long-term follow-up. However, the widespread adoption of MPO as a routine clinical biomarker faces significant challenges. Standardizing measurement techniques and determining the optimal timing of assessments are crucial for ensuring reliability and comparability across studies. Furthermore, while MPO shows promise as a complement to existing risk stratification protocols, questions remain regarding its superiority over troponins and its utility in stable coronary artery disease. Addressing these issues necessitates large-scale prospective cohort studies to clarify MPO’s comparative effectiveness alongside conventional biomarkers. Despite these challenges, MPO emerges as a potentially valuable addition to risk assessment strategies, particularly for patients with persistently negative troponin levels, helping guide therapeutic interventions and enhancing clinical decision-making in cardiovascular medicine.

Myeloperoxidase induces monocyte migration and activation after acute myocardial infarction.

Myocardial infarction (MI) is a significant contributor to morbidity and mortality worldwide. Many individuals who survive the acute event continue to experience heart failure (HF), with inflammatory and healing processes post-MI playing a pivotal role. Polymorphonuclear neutrophils (PMN) and monocytes infiltrate the infarcted area, where PMN release high amounts of the heme enzyme myeloperoxidase (MPO). MPO has numerous inflammatory properties and MPO plasma levels are correlated with prognosis and severity of MI. While studies have focused on MPO inhibition and controlling PMN infiltration into the infarcted tissue, less is known on MPO's role in monocyte function. Here, we combined human data with mouse and cell studies to examine the role of MPO on monocyte activation and migration. We revealed a correlation between plasma MPO levels and monocyte activation in a patient study. Using a mouse model of MI, we demonstrated that MPO deficiency led to an increase in splenic monocytes and a decrease in cardiac monocytes compared to wildtype mice (WT). In vitro studies further showed that MPO induces monocyte migration, with upregulation of the chemokine receptor CCR2 and upregulation of inflammatory pathways identified as underlying mechanisms. Taken together, we identify MPO as a pro-inflammatory mediator of splenic monocyte recruitment and activation post-MI and provide mechanistic insight for novel therapeutic strategies after ischemic injury.

Myeloperoxidase creates a permissive microenvironmental niche for the progression of multiple myeloma.

Expression of myeloperoxidase (MPO), a key inflammatory enzyme restricted to myeloid cells, is negatively associated with the development of solid tumours. Activated myeloid cell populations are increased in multiple myeloma (MM); however, the functional consequences of myeloid-derived MPO within the myeloma microenvironment are unknown. Here, the role of MPO in MM pathogenesis was investigated, and the capacity for pharmacological inhibition of MPO to impede MM progression was evaluated. In the 5TGM1-KaLwRij mouse model of myeloma, the early stages of tumour development were associated with an increase in CD11b+ myeloid cell populations and an increase in Mpo expression within the bone marrow (BM). Interestingly, MM tumour cell homing was increased towards sites of elevated myeloid cell numbers and MPO activity within the BM. Mechanistically, MPO induced the expression of key MM growth factors, resulting in tumour cell proliferation and suppressed cytotoxic T-cell activity. Notably, tumour growth studies in mice treated with a small-molecule irreversible inhibitor of MPO (4-ABAH) demonstrated a significant reduction in overall MM tumour burden. Taken together, our data demonstrate that MPO contributes to MM tumour growth, and that MPO-specific inhibitors may provide a new therapeutic strategy to limit MM disease progression.

Role of Myeloperoxidase in ROS Generation and Inflammation Response on Prostate Epithelial Cells.

Myeloperoxidase (MPO) has been reported in prostate tissue, and considering its pro-oxidant properties, this location might be linked to prostate pathology. The possibility that the glandular prostatic tissue might be the source of MPO and its potential inflammatory effects must be tested.Human prostate material was obtained from prostate biopsies and radical prostatectomies. Immunohistochemistry was performed using MPO-specific human antibody. In situ hybridization using MPO-specific probes and laser-assisted microdissection for quantitative real-time RT-PCR were performed to observe whether MPO is being produced in prostate tissue. Mass spectrometry on prostate biopsies was used to detect products of MPO activity in nucleic acids (DNA/RNA). MPO contribution to intracellular accumulation of ROS and interleukin-8 in prostatic epithelial cells was monitored in vitro. Immunohistochemistry confirmed cellular localization of MPO in epithelial cells of the prostate. The staining varied from light to high intensity. In situ hybridization did not address the presence of mRNA coding for MPO. No MPO-specific modifications on nucleic acids were detected. Mox-LDL was a major factor inducing ROS and cytokines production in prostatic epithelial cells.We did not demonstrate that MPO was synthetized by prostatic epithelial cells. However, in vitro experiments showed the ability of MPO to potentiate the ROS production and inflammation on prostate epithelial cells. Results do not allow us to demonstrate a role of MPO in prostate to date but further studies are mandatory to focus on the potential impact of MPO in the development of prostatic diseases.

Role of myeloperoxidase in atrial fibrillation and ischemic heart disease

Atrial fibrillation and ischemic heart disease are the key problems in cardiology. Despite of numerous clinical trials and researches underlying molecular biology remains uncertain. Atrial fibrillation and ischemic heart disease are often combined. During ischemic heart disease progression myocardial tissue structure are changing which lead to structural and electrophysiological remodeling and promote atrial fibrillation. It has been shown a crucial role of oxidative stress and chronic systemic inflammation in ischemic heart disease and atrial fibrillation. Myeloperoxidase (MPO) is one of marker of oxidative stress and inflammation that located in azurophilic granules of neutrophils and monocytes. There are a numerous articles showed a relation between MPO level and cardiovascular disease. MPO is a peroxidase enzyme that is important part of immune system. During disease MPO could facilitate chronic inflammation and local tissue damage through active oxygen forms. MPO releases after lysosome conjunction with phagosome. Oxygen reductase activity of MPO lead synthesis of hypochlorous acid that play role not only in organism protection from infection agents but in matrix transformation and fibrosis. It has been shown MPO can destabilize atherosclerotic plaque and modifies low- and high-density lipoproteins that promote atherosclerosis and ischemic heart diseaseу progression. This review summarizes current data about role of MPO in atrial fibrillation and ischemic heart disease pathogenesis.

The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis.

The risk of idiosyncratic drug-induced agranulocytosis (IDIAG) markedly constrains the use of clozapine, a neuroleptic with unparalleled efficacy. Most clozapine patients experience an early inflammatory response, likely a necessary step in IDIAG onset. However, most patients do not progress to IDIAG, presumably because of the requirement of specific human leukocyte antigen (HLA) haplotypes, T cell receptors, and other unknown factors. We established that clozapine activates inflammasomes and that myeloperoxidase bioactivation of clozapine generates neoantigens, but the connection between these early mechanistic events remained unknown and, thus, was the aim of this work. We found that the myeloperoxidase inhibitor PF-1355 attenuated myeloperoxidase activity in phorbol myristate acetate (PMA)-differentiated THP-1 macrophages, and it also attenuated clozapine-induced release of inflammatory mediators (e.g., IL-1β, CXCL1, and C-reactive protein). In vivo, pretreatment of Sprague Dawley rats with PF-1355 significantly attenuated clozapine-induced increases in neutrophil mobilization from the bone marrow to the blood and spleen, as determined using differential blood counts and flow cytometry. Moreover, the clozapine-triggered release of inflammatory mediators (e.g., IL-1β, calprotectin, CXCL1, and α-1-acid glycoprotein) from the liver, spleen, and bone marrow was dampened by myeloperoxidase inhibition. These data support the working hypothesis that oxidation of clozapine to a reactive metabolite by myeloperoxidase is critical for induction of the inflammatory response to clozapine. Ultimately, a better mechanistic understanding of the early events involved in the immune response to clozapine may elucidate ways to prevent IDIAG, enabling safer, more frequent therapeutic use of this and potentially other highly efficacious drugs.

Trichomonas gallinae induces heterophil extracellular trap formation in pigeons.

Avian trichomonosis is a worldwide and cross-species epidemic, and the infection in pigeons is particularly severe. Although the disease causes a serious threat to poultry health resulting in significant economic losses, the relationship between Trichomonas gallinae (T. gallinae) and host innate immunity is still not clear. Extracellular traps (ETs) are an innate immunity response to parasitic infections. However, whether host cells can produce ETs after T. gallinae infection has not yet been reported. In the present study, the ability of T. gallinae to induce the production of heterophil extracellular traps (HETs) in pigeons was examined. T. gallinae-induced HETs were observed by scanning electron microscopy (SEM) and the main components of HETs were detected by fluorescence confocal microscopy. Changes in reactive oxygen species (ROS) and lactate dehydrogenase (LDH) were tested during the HETosis. A quantitative analysis of T. gallinae-induced HETs, the role of myeloperoxidase (MPO), store-operated Ca (2+) entry (SOCE), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in T. gallinae-induced HET formation were conducted by inhibitor assays. The results showed that T. gallinae induced ET formation in pigeon heterophils. ETs consisted of a DNA skeleton, neutrophil elastase (NE), MPO, and Histone3 (H3). T. gallinae-induced HETs formation in a dose- and time-dependent process. The release of T. gallinae-induced HETs depends on MPO, SOCE, and NADPH oxidase. Furthermore, after T. gallinae stimulated pigeon heterophils, ROS production was significantly increased, while no significant differences in the LDH activity were observed.

Properties and functions of myeloperoxidase and its role in ovarian cancer

Background: Elevated levels of myeloperoxidase in body fluids are increasingly being used as an indicator for the diagnosis of cancer. Aim of the study: The aim of this study was to review the literature on the physical and chemical properties of myeloperoxidase, its role in carcinogenesis, the role of tumor-associated neutrophils in cancer, and the role of myeloperoxidase in ovarian cancer. Material and methods: The research literature published between January 1999 and December 2019 was reviewed. The properties and role of myeloperoxidase in the development of ovarian cancer were selected from publications available in selected online databases, including MEDLINE, PubMed, Scopus, and Web of Science. Searches were performed using the following word combinations: “myeloperoxidase”, “ovarian cancer”, “reactive oxygen species”, “expression”, “polymorphism”, and “tumor-associated neutrophils”. Results: Thirty-five scientific articles were included in the final review. Of the 35 articles, 11 discussed the role of myeloperoxidase in carcinogenesis, and five discussed its role in the development of ovarian cancer. Conclusions: Elevated myeloperoxidase levels are associated with many types of cancer, including ovarian cancer. In the studied group of invasive ovarian tumors, up to 65% exhibited elevated levels of myeloperoxidase. Continued research on myeloperoxidase expression in ovarian cancer cells is vital and warranted.

Myeloperoxidase as prognostic factor for atrial fibrillation development in patients with ST-segment elevation myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Background Arrhythmia is among the most common and severe myocardial infarction complications. Myeloperoxidase as an important immune factor can be linked to atrial fibrillation (AF) development. Previous studies indicated myeloperoxidase (MPO) as a significant mortality predictor in ST-segment elevation myocardial infarction (STEMI). The MPO role in prognosis for adverse clinical outcomes, as atrial fibrillations in STEMI patients remains not fully understood. The purpose of the investigation was to examine the MPO in prognosis of adverse outcomes presented by atrial fibrillations in patients with STEMI. Methods The study included 233 STEMI patients, 112 males, 121 females, and average age 67.87±7.11 years. Follow-up period was 14 days. Adverse outcome was observed and included atrial fibrillations. Plasma MPO levels were determined by ELISA, MPO was collected on admission. Results Patients with indicated adverse effects showed significantly increased MPO levels compared to those without ones, 169.91 IQR [89.45; 201.98] ng/ml vs 81.4 [33.91;181.29] ng/ml; p < 0.001. A ROC analysis determined a MPO cut-off value for arrhythmia (AF) development of 176.53 ng/ml with a sensitivity of 71.1% and specificity of 77.6%, AUC 0.732; 95 % CI 0.677-0.782; p <0.001. Elevated MPO concentration was a significant predictor for AF (OR 1.115; 95% CI: 1.007-1.841; p<0.001). Even adjusted for age and sex MPO remained significantly predictive for arrhythmia development. Conclusions The study suggests that increased levels of MPO are associated with the higher risk of atrial fibrillation. MPO could be a possible significant factor for therapy optimization in high-risk STEMI patients.

Role of myeloperoxidase in inflammation and atherosclerosis (Review)

Myeloperoxidase (MPO) belongs to the heme peroxidase family, which includes a set of enzymes with potent oxidoreductase activity. MPO is considered an important part of the innate immune system's microbicidal arm and is secreted by neutrophils and macrophages. Interestingly, this enzyme has been implicated in the pathogenesis of several diseases including atherosclerosis. MPO is ubiquitous in atherosclerotic lesions and contributes to the initiation and progression of the disease primarily by oxidizing low-density lipoprotein (LDL) particles. MPO is the only human enzyme with the ability to produce hypochlorous acid (HOCl) at physiological chloride concentrations and HOCl-LDL epitopes were shown to be present inside atheromatous lesions making it a physiologically relevant model for the oxidation of LDL. It has been shown that MPO modified LDL is not able to bind to the native LDL receptor and is recognized instead by scavenger receptors on both endothelial cells and macrophages, which can lead to endothelial dysfunction and foam cell formation, respectively; both of which are instrumental in the progression of the disease. Meanwhile, several studies have proposed MPO as a biomarker for cardiovascular diseases where high levels of this enzyme were linked to an increased risk of developing coronary artery disease. Overall, there is sufficient evidence supporting the value of MPO as a crucial player in health and disease. Thus, future research should be directed towards investigating the still unknown processes associated with this enzyme. This may assist in better understanding the pathophysiological role of MPO, as well in the development of therapeutic strategies for protecting against the deleterious effects of MPO in numerous pathologies such as atherosclerosis.

Myeloperoxidase exerts anti-tumor activity in glioma after radiotherapy.

BackgroundHost immune response is a critical component in tumorigenesis and immune escape. Radiation is widely used for glioblastoma (GBM) and can induce marked tissue inflammation and substantially alter host immune response. However, the role of myeloperoxidase (MPO), a key enzyme in inflammation and host immune response, in tumorigenesis after radiotherapy is unclear. In this study, we aimed to determine how post-radiation MPO activity influences GBM and outcome.MethodsWe injected C57BL/6J or MPO-knockout mice with 005 mouse GBM stem cells intracranially. To observe MPO's effects on post-radiation tumor progression, we then irradiated the head with 10 Gy unfractionated and treated the mice with a specific MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH), or vehicle as control. We performed semi-quantitative longitudinal molecular MRI, enzymatic assays and flow cytometry to assess changes in inflammatory response and tumor size, and tracked survival. We also performed cell culture experiments in murine and human GBM cells to determine the effect of MPO on these cells.ResultsBrain irradiation increased the number of monocytes/macrophages and neutrophils, and boosted MPO activity by ten-fold in the glioma microenvironment. However, MPO inhibition dampened radiation-induced inflammation, demonstrating decreased MPO-specific signal on molecular MRI and attenuated neutrophil and inflammatory monocyte/macrophage recruitment to the glioma. Compared to saline-treated mice, both ABAH-treated and MPO-knockout mice had accelerated tumor growth and reduced survival. We further confirmed that MPO decreased tumor cell viability and proliferation in cell cultures.ConclusionLocal radiation to the brain initiated an acute systemic inflammatory response with increased MPO-carrying cells both in the periphery and the GBM, resulting in increased MPO activity in the tumor microenvironment. Inhibition or absence of MPO activity increased tumor growth and decreased host survival, revealing that elevated MPO activity after radiation has an anti-tumor role.

The role of myeloperoxidase as a diagnostic and prognostic factor in cardiovascular pathology (acute coronary syndrome)

Myeloperoxidase is one of the key enzymes involved in oxidative stress and inflammation. Its elevated levels are determined in a wide range of both acute and chronic forms of cardiovascular diseases. The inflammation results in the release of the enzyme from the white blood cells to form products such as hypochlorous acid, which in turn can have a negative effect on the target proteins. Inconsistent evidence on the predictive role of this biomarker in diseases of the circulatory system generates scientific interest and provokes further research in this direction. The aim of this review is to analyze the scientific literature data on myeloperoxidase as a possible clinical use for the diagnosis and risk stratification of patients with саrdiovascular diseases. Materials and methods. Searching and generalization of data from leading specialized sources, which are indexed by scientific databases PubMed, SCOPUS, Web of Science. Results. The results of the studies indicate that myeloperoxidase is actively involved in the pathophysiology of cardiovascular diseases through participation in oxidative stress and inflammation, excessive production of proatherogenic lipoproteins, changes in nitric oxide activity, endothelial dysfunction, and due to the effect on the instability of atherosclerotic plaques. In patients with cardiovascular diseases, including ischemic heart disease, the concentration of the indicated protein is increased and is often associated with a poor prognosis, including an increased risk of mortality. Myeloperoxidase metabolites are often the factors that contribute to cell damage under conditions of ischemia. The review also considers the relationship of the enzyme with the development of restenosis and the effectiveness of revascularization after percutaneous coronary intervention. Conclusions. The presented data mainly define myeloperoxidase as a significant marker for predicting long-term follow-up results and the development of serious adverse cardiovascular events, mortality in patients with cardiovascular disease. At the same time, despite the great achievements in disclosing the complex effects of myeloperoxidase, inconsistency in the available results is noteworthy. This controversy necessitates further research to elucidate and reveal the full clinical potential of myeloperoxidase in patients with cardiovascular pathology.

Neutrophil-Derived Myeloperoxidase Facilitates Both the Induction and Elicitation Phases of Contact Hypersensitivity.

BackgroundAllergic contact dermatitis (ACD) is a common skin disorder affecting an estimated 15-20% of the general population. The mouse model of ACD is contact hypersensitivity (CHS), which consists of two phases: induction and elicitation. Although neutrophils are required for both CHS disease phases their mechanisms of action are poorly understood. Neutrophils release myeloperoxidase (MPO) that through oxidation of biomolecules leads to cellular damage.ObjectivesThis study investigated mechanisms whereby MPO contributes to CHS pathogenesis.MethodsCHS was induced in mice using oxazolone (OX) as the initiating hapten applied to the skin. After 7 days, CHS was elicited by application of OX to the ear and disease severity was measured by ear thickness and vascular permeability in the ear. The role of MPO in the two phases of CHS was determined utilizing MPO-deficient mice and a specific MPO inhibitor.ResultsDuring the CHS induction phase MPO-deficiency lead to a reduction in IL-1β production in the skin and a subsequent reduction in migratory dendritic cells (DC) and effector T cells in the draining lymph node. During the elicitation phase, inhibition of MPO significantly reduced both ear swelling and vascular permeability.ConclusionMPO plays dual roles in CHS pathogenesis. In the initiation phase MPO promotes IL-1β production in the skin and activation of migratory DC that promote effector T cell priming. In the elicitation phase MPO drives vascular permeability contributing to inflammation. These results indicate that MPO it could be a potential therapeutic target for the treatment of ACD in humans.

THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

Abstract Neutrophils are short-lived immune cells that represent the major cell type recruited to the inflamed bowel releasing their azurophilic granules containing enzymes myeloperoxidase (MPO). Fecal and serum MPO levels has previously been shown to correlate to disease severity in IBD patients. MPO, in the presence of H2O2 and free Cl- undergoes a halogenation cycle, yielding the two-electron oxidant, hypochlorous acid (HOCl) - a potent bactericidal agent. However, chronic intestinal exposure to MPO/HOCl due to perpetual inflammation may cause secondary host-tissue injury and cell death. Neutrophil Extracellular Trap (NET)osis is a specialised form of neutrophil death where MPO is entrapped in a DNA scaffold and continues to elicit HOCl activity and may further contribute to host-tissue injury. We investigated the presence of NETs in surgically excised ileum samples from CD and healthy patients using advanced confocal microscopic techniques and found MPO, Neutrophil Elastase (NE) and Citrullinated Histone h3 (CitH3) - critical components of NET formation, individually positively correlate to the severity of histopathological intestinal injury. Furthermore, multiplex Opal™ IHC performed using LMS880 Airyscan-moduled microscopy with z-stacking revealed colocalization of NE, MPO, CitH3 and DAPI indicating the extensive presence of NETs in severely affected CD tissue. Using two pharmacological inhibitors of MPO in a dextran sodium sulphate (DSS) model of murine colitis, we demonstrated the pathological role of MPO in experimental colitis. MPO inhibitors, TEMPOL and AZD3241 delivered via daily i.p significantly rescued the course of colitis by abrogating clinical indices including body weight loss, disease activity index, inhibiting serum peroxidation, and preserving colon length, while significantly mitigating histoarchitectural damage associated with DSS-induced colitis. We also showed that MPO inhibition decreased neutrophil migration to the gut, suggesting MPO may play a role in perpetuating the inflammatory cell by further recruiting cells to the inflamed gut. Collectively, we have shown for the first time that MPO is not only an important clinical marker of disease severity but may also play a critical role in perpetuating host-tissue damage and inflammation.

Dysfunctional High-density Lipoprotein: The Role of Myeloperoxidase and Paraoxonase-1

Bentham Science - STM publisher of online and print journals, and related print/online book series. Bentham Science answers the information needs of scientists in the fields of pharmaceutical, biomedical, medical, engineering, technology, computer and social sciences.

Myeloperoxidase Modulates Hydrogen Peroxide Mediated Cellular Damage in Murine Macrophages

Myeloperoxidase (MPO) is involved in the development of many chronic inflammatory diseases, in addition to its key role in innate immune defenses. This is attributed to the excessive production of hypochlorous acid (HOCl) by MPO at inflammatory sites, which causes tissue damage. This has sparked wide interest in the development of therapeutic approaches to prevent HOCl-induced cellular damage including supplementation with thiocyanate (SCN−) as an alternative substrate for MPO. In this study, we used an enzymatic system composed of glucose oxidase (GO), glucose, and MPO in the absence and presence of SCN−, to investigate the effects of generating a continuous flux of oxidants on macrophage cell function. Our studies show the generation of hydrogen peroxide (H2O2) by glucose and GO results in a dose- and time-dependent decrease in metabolic activity and cell viability, and the activation of stress-related signaling pathways. Interestingly, these damaging effects were attenuated by the addition of MPO to form HOCl. Supplementation with SCN−, which favors the formation of hypothiocyanous acid, could reverse this effect. Addition of MPO also resulted in upregulation of the antioxidant gene, NAD(P)H:quinone acceptor oxidoreductase 1. This study provides new insights into the role of MPO in the modulation of macrophage function, which may be relevant to inflammatory pathologies.

Antineutrophil Cytoplasmic Antibody in Lupus Nephritis: Correlation with Clinicopathological Characteristics and Disease Activity.

Lupus nephritis (LN) represents 40%-50% of all systemic lupus erythematosus (SLE) patients, and rapidly progressive glomerulonephritis is associated with significant morbidity and mortality. Antineutrophil cytoplasmic antibody (ANCA) might be involved in the pathogenesis of LN. We evaluated the role of myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA, and anti-glomerular basement membrane autoantibodies (anti-GBM autoAb) for the diagnosis of LN. In this cross-sectional study, 95 SLE patients were divided into 2 subgroups: LN group (n = 60) and non-LN group (n = 35). For further analysis, we subclassified the LN group into ANCA- positive (n = 16) and ANCA-negative (n = 44) LN patients. The entire Non-LN group was ANCA- negative. The SLE disease activity index (SLEDAI) was reported for each patient. Determination of MPO-ANCA, PR3-ANCA, and anti-GBM autoAb was performed using a novel multiplex bead-based technology in all patients. Data analyses were done using SPSS, version 20. Approval was obtained from the institutional review board of Zagazig University (ZU-IRB#6000). Of 95 patients with SLE, 16 patients (16.84%) had ANCA-positive LN, all of which were MPO-ANCA. There was a positive correlation between MPO-ANCA and SLEDAI, as well as with class IV LN. Receiver operating characteristic analyses revealed that the sensitivity and specificity of MPO-ANCA were 81.3% and 99.8%, respectively, in discriminating LN from systemic lupus without nephritis. MPO-ANCA level was significantly correlated with SLEDAI, inflammatory markers, kidney function tests, and LN class IV.

Dysfunctional High-density Lipoprotein: The Role of Myeloperoxidase and Paraoxonase-1.

Low circulating high-density lipoproteins (HDL) are not only defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte- derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation and then acts as a protective factor against ASCVD. It is noteworthy that recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, a high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview of in vitro and experimental animal models, finally focusing on clinical evidence from a cohort of patients with ASCVD and metabolic syndrome.

Significance of myeloperoxidase plasma levels as a predictor for cardiac resynchronization therapy response

ObjectivesThis study aimed to determine if changes in myeloperoxidase (MPO) levels correlate with response to cardiac resynchronization therapy (CRT) and the potential role of MPO as a predictor of response to CRT.BackgroundCRT is a well-established treatment option in chronic heart failure (CHF) with 50–80% of patients benefiting. Inflammation and oxidative stress play a key role in CHF pathophysiology. Previous studies have demonstrated increased levels of MPO in CHF patients, but the correlation with CRT response remains incompletely understood.Methods Fifty-three patients underwent CRT implantation. During follow-up, patients were divided into two groups, responders and non-responders to CRT, based on improved physical capacity and NYHA classification. Levels of MPO and NT-pro-brain-natriuretic-peptide (NT-proBNP) were determined prior to implantation, 30 and 90 days after. Physical capacity, including a 6-min walking-test, NYHA class, and LVEF were evaluated at baseline and during follow-up.Results Thirty-four patients (64%) responded to CRT, showing improved physical capacity and LVEF. All responders revealed a significant decrease of MPO levels (503.8 ng/ml vs. 188.4 ng/ml; p < 0.001). Non-responding patients did not show any significant changes in clinical parameters or MPO levels (119.6 ng/ml vs. 134.3 ng/ml; p = 0.672) during follow-up. At baseline, physical capacity and NYHA class, as well as MPO levels differed significantly between both groups (p < 0.001). A ROC analysis identified an MPO cut-off value for response to CRT of 242 ng/ml with a sensitivity of 93.5% and specificity of 71.4%. There was a strong correlation between MPO and improvement of LVEF (Spearman’s rho: − 0.453; p = 0.005) and physical capacity (Spearman’s rho: − 0.335; p = 0.042).ConclusionsResponse to CRT and course of MPO levels correlate significantly. MPO levels differ between responders and non-responders prior to CRT, which may indicate an additional value of MPO as a predictor for CRT response. Further randomized studies are required to confirm our data in larger patient cohorts.