Myeloperoxidase: A versatile mediator of endothelial dysfunction and therapeutic target during cardiovascular disease

Maiocchi, Sophie; Ku, Jacqueline M; Thai, Thuan; Chan, Enoch; Rees, Martin D.; Thomas, Shane R.

doi:10.1016/j.pharmthera.2020.107711

Cited by 41 publications

(37 citation statements)

References 614 publications

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“…However, all five peptides could form hydrophobic interactions with one of the catalytic residues (Arg239) of MPO. Besides, all five peptides could interact with the heme group (Hec606) through hydrophobic interactions ( Table 2 ); the heme group is a cofactor in the active site of MPO [ 42 ]. Based on the interactions with both catalytic residue Arg239 and the heme group of MPO, all the five peptides are potential MPO inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach

et al. 2021

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Some seed-derived antioxidant peptides are known to regulate cellular modulators of ROS production, including those proposed to be promising targets of anticancer therapy. Nevertheless, research in this direction is relatively slow owing to the inevitable time-consuming nature of wet-lab experimentations. To help expedite such explorations, we performed structure-based virtual screening on seed-derived antioxidant peptides in the literature for anticancer potential. The ability of the peptides to interact with myeloperoxidase, xanthine oxidase, Keap1, and p47phox was examined. We generated a virtual library of 677 peptides based on a database and literature search. Screening for anticancer potential, non-toxicity, non-allergenicity, non-hemolyticity narrowed down the collection to five candidates. Molecular docking found LYSPH as the most promising in targeting myeloperoxidase, xanthine oxidase, and Keap1, whereas PSYLNTPLL was the best candidate to bind stably to key residues in p47phox. Stability of the four peptide-target complexes was supported by molecular dynamics simulation. LYSPH and PSYLNTPLL were predicted to have cell- and blood-brain barrier penetrating potential, although intolerant to gastrointestinal digestion. Computational alanine scanning found tyrosine residues in both peptides as crucial to stable binding to the targets. Overall, LYSPH and PSYLNTPLL are two potential anticancer peptides that deserve deeper exploration in future.

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Section: Resultsmentioning

confidence: 99%

Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach

et al. 2021

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“…Recent studies have pointed to several MPO inhibitors for the prevention and treatment of atherosclerotic cardiovascular disease, such as PF-1355, AZM198, azo radical, and thiocyanate ( 29 ). Targeting MPO has the potential to become one of the most promising therapies for coronary heart disease and other atherosclerotic cardiovascular diseases, such as PF-06282999 ( 8 ), which has effective and selective MPO inhibition properties, and has been advanced into clinical trials in human pharmacokinetics, safety, tolerance, and MPO inhibition studies ( 30 ). However, there are still some challenges to consider in the application of MPO inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Correlation Analysis of Plasma Myeloperoxidase Level With Global Registry of Acute Coronary Events Score and Prognosis in Patients With Acute Non-ST-Segment Elevation Myocardial Infarction

Zhang

Wang

et al. 2022

Front. Med.

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BackgroundMyeloperoxidase (MPO) and global registry of acute coronary events (GRACE) risk scores were independently used to predict adverse outcomes in patients with acute coronary syndrome (ACS). However, the relationship between MPO level and GRACE score, and whether the combination of MPO and GRACE can better predict major adverse cardiovascular events (MACEs) in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI), have not been previously investigated.MethodsA prospective cohort of 271 consecutive patients with NSTEMI were enrolled in this study. Plasma MPO levels were measured by ELISA. Baseline demographic and clinical information was collected, and GRACE scores were calculated at admission. The correlation between MPO and MACEs was evaluated with the GRACE score during a 1-year follow-up.ResultsThe results showed that plasma MPO level was correlated with inflammatory indices (including high-sensitivity C-reactive protein (hs-CRP), leukocyte count, neutrophil count, and fibrinogen), N-terminal pro-B type natriuretic peptide (NT-proBNP), and hypersensitive troponin T (hsTNT) levels (All p-values < 0.05), and there was a statistically significant correlation between plasma MPO level and GRACE score (r = 0.22, p < 0.001). The Kaplan-Meier curves showed that patients with higher MPO levels had lower event-free survival (Log-rank P < 0.001). The multivariate Cox model showed MPO was an independent risk factor for 1-year MACEs in patients with NSTEMI (HR: 3.85, 95% CI: 1.4–10.6, p = 0.009). Subgroup analysis showed that MPO was a strong prognostic biomarker, and its prognostic value was more significant in patients with age >65 years and N-terminal pro-B type natriuretic peptide (NT-proBNP) level >1,000 pg/ml. For high-risk patients with GRACE scores, a higher level of MPO has a higher prognostic value.ConclusionElevated plasma MPO levels are associated with high inflammatory status and GRACE scores in patients with NSTEMI. For high-risk patients with GRACE scores, higher MPO levels were more predictive of future MACEs.

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“…Activated and invading/recruited neutrophils (containing up to 5% MPO of total cell protein content) play potential roles in the initiation and progression of atherosclerosis and other CVDs [ 9 , 69 ] including cardiac damage [ 3 , 70 ]. Thus, MPO has gained significant attention as an oxidative mediator of reperfusion injury, adverse ventricular remodelling, and atrial fibrillation [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes

et al. 2021

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Neutrophil-derived myeloperoxidase (MPO) and its potent oxidant, hypochlorous acid (HOCl), gained attention as important oxidative mediators in cardiac damage and dysfunction. As cardiomyocytes generate low-density lipoprotein (LDL)-like particles, we aimed to identify the footprints of proatherogenic HOCl-LDL, which adversely affects cellular signalling cascades in various cell types, in the human infarcted myocardium. We performed immunohistochemistry for MPO and HOCl-LDL in human myocardial tissue, investigated the impact of HOCl-LDL on electrophysiology and contractility in primary cardiomyocytes, and explored underlying mechanisms in HL-1 cardiomyocytes and human atrial appendages using immunoblot analysis, qPCR, and silencing experiments. HOCl-LDL reduced ICa,L and IK1, and increased INaL, leading to altered action potential characteristics and arrhythmic events including early- and delayed-afterdepolarizations. HOCl-LDL altered the expression and function of CaV1.2, RyR2, NCX1, and SERCA2a, resulting in impaired contractility and Ca2+ homeostasis. Elevated superoxide anion levels and oxidation of CaMKII were mediated via LOX-1 signaling in HL-1 cardiomyocytes. Furthermore, HOCl-LDL-mediated alterations of cardiac contractility and electrophysiology, including arrhythmic events, were ameliorated by the CaMKII inhibitor KN93 and the INaL blocker, ranolazine. This study provides an explanatory framework for the detrimental effects of HOCl-LDL compared to native LDL and cardiac remodeling in patients with high MPO levels during the progression of cardiovascular disease.

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Myeloperoxidase: A versatile mediator of endothelial dysfunction and therapeutic target during cardiovascular disease

Cited by 41 publications

References 614 publications

Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach

Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach

Correlation Analysis of Plasma Myeloperoxidase Level With Global Registry of Acute Coronary Events Score and Prognosis in Patients With Acute Non-ST-Segment Elevation Myocardial Infarction

Hypochlorite-Modified LDL Induces Arrhythmia and Contractile Dysfunction in Cardiomyocytes

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