Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: A potential carbamylation route involved in the formation of atherosclerotic plaques?

Protein carbamylation by cyanate is a post-translational modification associated with several (patho)physiological conditions, including cardiovascular disorders. However, the biochemical pathways leading to protein carbamylation are incompletely characterized. This work demonstrates that the heme protein myeloperoxidase (MPO), which is secreted at high concentrations at inflammatory sites from stimulated neutrophils and monocytes, is able to catalyze the two-electron oxidation of cyanide to cyanate and promote the carbamylation of taurine, lysine, and low-density lipoproteins.

Exposure of endothelial cells to physiological levels of myeloperoxidase-modified LDL delays pericellular fibrinolysis.

Background: Blood fluidity is maintained by a delicate balance between coagulation and fibrinolysis. The endothelial cell surface is a key player in this equilibrium and cell surface disruptions can upset the balance. We investigated the role of pericellular myeloperoxidase oxidized LDLs (Mox-LDLs) in this balance.

Safety of a fixed-dose combination of fenofibrate/pravastatin 160 mg/40 mg in patients with mixed hyperlipidaemia: a pooled analysis from a database of clinical trials.

Background: Fenofibrate can be prescribed concomitantly with an HMG-CoA reductase inhibitor (statin) to improve achievement of lipid goals in patients with atherogenic mixed hyperlipidaemia. However, some safety concerns, particularly an increased risk of myopathy, have been reported when these drugs are taken together.

Objective: The aim of this analysis was to assess the general safety and tolerability of a fenofibrate/pravastatin (FF/PRA) 160 mg/40 mg fixed-dose combination (FDC) capsule based on a pooled database of phase III clinical trials in patients with mixed hyperlipidaemia.

Long-term safety and efficacy of fenofibrate/pravastatin combination therapy in high risk patients with mixed hyperlipidemia not controlled by pravastatin monotherapy.

Objective: To assess the long-term safety and efficacy of a fenofibrate/pravastatin 160/40 mg fixed-dose combination in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40 mg monotherapy.

Study Design And Methods: After an 8-week pravastatin 40 mg and diet run-in period, high-risk patients (n = 248) with low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL and triglycerides (TG) ≥ 150 and ≤400 mg/dL, were randomized to fenofibrate/pravastatin combination therapy or to pravastatin monotherapy for 12 weeks, followed by an open-label, 52-week safety phase on the combination therapy.

Results: Of the 224 patients who continued after the double-blind phase, 211 completed the one-year safety period.

Optimization of apolipoprotein-B-100 sequence coverage by liquid chromatography-tandem mass spectrometry for the future study of its posttranslational modifications.

Proteomic applications have been increasingly used to study posttranslational modifications of proteins (PTMs). For the purpose of identifying and localizing specific but unknown PTMs on huge proteins, improving their sequence coverage is fundamental. Using liquid chromatography coupled to mass spectrometry (LC-MS/MS), peptide mapping of the native apolipoprotein-B-100 was performed to further document the effects of oxidation.

Structure-based design, synthesis, and pharmacological evaluation of 3-(aminoalkyl)-5-fluoroindoles as myeloperoxidase inhibitors.

Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor.

Efficacy and safety of adding fenofibrate 160 mg in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40 mg monotherapy.

Patients with mixed hyperlipidemia and at high risk of coronary heart disease may not achieve recommended low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL) cholesterol goals on statin monotherapy. This study was designed to evaluate the efficacy and safety of a fenofibrate 160 mg/pravastatin 40 mg fixed-dose combination therapy in high-risk patients not at their LDL cholesterol goal on pravastatin 40 mg. In this 12-week, multicenter, randomized, double-blind, double-dummy, parallel-group study, after a run-in on pravastatin 40 mg, 248 patients were randomly assigned to fenofibrate/pravastatin combination therapy or to pravastatin monotherapy.

Effects of raloxifene treatment on the phenotype of blood monocytes.

Raloxifene (RLX), a selective oestrogen receptor modulator, has oestrogen-agonist effects on bone, lipoproteins, and homocysteine and oestrogen-antagonist activity in the breast and uterus, positioning it as a potential drug for long-term prevention of coronary heart disease in postmenopausal women. To further evaluate its influence on cardiovascular risk factors, we studied the effects of 60 mg/day RLX on serum lipid levels, inflammatory (high-sensitivity C-reactive protein, and coagulation (fibrinogen) markers, monocytes, and fibrinolysis in 15 healthy postmenopausal women. Markers were measured at baseline, after 1 month without treatment, and after 3 months of treatment.

Coronary stenting is associated with an acute increase in plasma myeloperoxidase in stable angina patients but not in patients with acute myocardial infarction.

Background: Myeloperoxidase (MPO) has emerged as a critical mediator in the physiopathology of atherosclerosis from plaque formation and growth until destabilization and rupture leading to acute coronary syndrome (ACS). Using coronary stenting as a model of plaque injury, we aimed to determine the evolution of systemic MPO levels following coronary stenting in stable angina patients and in patients with acute myocardial infarction (AMI).

Methods: Plasma levels of MPO, lactoferrin, interleukin (IL)-6, C-reactive protein and PMN counts were assessed in 13 patients with Non-ST-elevation myocardial infarction (NSTEMI) (Group A) and in 29 patients with stable angina pectoris (Group B), undergoing coronary stenting.

Effects of phosphodiesterase inhibitors on the inflammatory response of endothelial cells stimulated by myeloperoxidase-modified low-density lipoprotein or tumor necrosis factor alpha.

Background: Sildenafil, vardenafil, and tadalafil are phosphodiesterase type 5 inhibitors (PDE5-Is) usually used in the treatment of erectile dysfunction (ED). Previously, we have shown the presence of myeloperoxidase-modified low-density lipoprotein (Mox-LDL) in the penises of patients with ED, and we have shown the impact of Mox-LDL on cyclic monophosphate (cGMP) level. In vitro, Mox-LDL triggered the inflammatory response by increasing the release of both interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) by endothelial cells (ECs) and monocytes respectively.

Belgian expert opinion: how to reduce the residual risk in atherogenic dyslipidaemic patients: place of fibrates.

The demographics of dyslipidaemia have changed towards a more complex atherogenic dyslipidaemia involving increased levels of LDL-C, in particular highly atherogenic small dense particles, hypertriglyceridaemia and low HDL, together with increased levels of markers of cardiovascular inflammation, thrombogenesis and endothelial dysfunction. Statins were shown to significantly lower cardiovascular morbidity and mortality, but there still remains a high residual risk in dyslipidaemic patients, in particular with metabolic syndrome, type 2 diabetes, or low HDL levels. Fibrates have been shown to reduce plasma triglycerides and increase HDL-C, while improving inflammation, thrombogenesis and endothelial dysfunction.

Monocyte-platelet complexes on CD14/CD16 monocyte subsets: relationship with ApoA-I levels. A preliminary study.

The adhesion of the monocytes to the endothelium and their extravasation into the intima are key steps in atherogenesis. Studies showed the essential role of L-selectin (CD62-L), expressed by the monocytes, and the platelets by forming complexes with monocytes. The delipided apolipoprotein (Apo) A or high-density lipoprotein (HDL) has antiinflammatory effects on monocytes and can bind platelets (monocyte-platelet complexes [MPCs]).

Development and validation of a screening procedure for the assessment of inhibition using a recombinant enzyme.

Myeloperoxidase (MPO, E.C. 1.

Sleep restriction increases white blood cells, mainly neutrophil count, in young healthy men: a pilot study.

Objectives: This study examines the effects of sleep restricted to four hours for three consecutive nights on blood parameters, known to be associated with cardiovascular risk, in young healthy men.

Material And Methods: Eight young healthy men (age 24.5 +/- 3.

Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification.

The development of myeloperoxidase (MPO) inhibitors has been conducted using flufenamic acid as a lead compound. Computational docking of the drug and its analogs in the MPO active site was first attempted. Several molecules were then synthesized and assessed using three procedures for the measurement of their inhibiting activity: (i) the taurine assay, (ii) the accumulation of compound II, and (iii) the LDL oxidation by ELISA.

Comparison of short-term renal effects and efficacy of rosuvastatin 40 mg and simvastatin 80 mg, followed by assessment of long-term renal effects of rosuvastatin 40 mg, in patients with dyslipidemia.

Background: An open-label, randomized, multinational, parallel-group trial compared the short-term (6-week) renal effects of rosuvastatin 40 mg and simvastatin 80 mg in patients with hypercholesterolemia. Most patients (93%) then entered an optional open-label extension (OLE) to assess long-term (up to 72 weeks) renal effects of rosuvastatin.

Methods: After dietary lead-in, 626 patients were randomized to rosuvastatin or simvastatin for 6 weeks, followed by an optional, single-arm OLE to assess longer-term effects of rosuvastatin on renal function, safety, and efficacy.

Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs: flufenamic acid and its 5-chloro-derivative directly interact with a recombinant human myeloperoxidase to inhibit the synthesis of hypochlorous acid.

The present in vitro study was designed to assess the inhibition of the myeloperoxidase (MPO)/H(2)O(2)/Cl(-) system by several non steroidal anti-inflammatory drugs (NSAIDs) of the oxicam family and of nimesulide and to compare their effect with flufenamic acid in order to investigate their influence on the chlorinating activity of MPO as a protective mechanism during chronic inflammatory syndromes. The inhibition of the system was assessed by measurement of the taurine chlorination while the accumulation of compound II was used to investigate the mechanism of inhibition. The oxidation products of NSAIDs by the MPO/H(2)O(2)/Cl(-) system were identified and flufenamic acid and derivatives were also assessed in the inhibition of LDL oxidation in two models.

Efficacy of atorvastatin after LDL-cholesterol-based dose selection in high risk dyslipidaemic patients: results of the target dose study.

Background: Hypercholesterolaemia is one of the major risk factors for the development of coronary heart disease (CHD). European guidelines emphasize the importance of reducing low-density lipoprotein cholesterol (LDL-C) levels below 115 mg/dL (3.0 mmol/L) in patients with high CHD risk.

Triggering of inflammatory response by myeloperoxidase-oxidized LDL.

The oxidation theory proposes that LDL oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis in triggering inflammation. In contrast to the copper-modified LDL, there are few studies using myeloperoxidase-modified LDL (Mox-LDL) as an inflammation inducer. Our aim is to test whether Mox-LDL could constitute a specific inducer of the inflammatory response.

Presence of LDL modified by myeloperoxidase in the penis in patients with vascular erectile dysfunction: a preliminary study.

Objective: Erectile dysfunction (ED) is a major vascular disorder. Atherosclerosis is closely related to lipoprotein metabolism and especially, oxidative modifications of low-density lipoproteins (LDLs), which are involved in early development of the atherosclerotic lesions. Current major questions include how LDLs are oxidised (OxLDL) in vivo.

Captopril inhibits the oxidative modification of apolipoprotein B-100 caused by myeloperoxydase in a comparative in vitro assay of angiotensin converting enzyme inhibitors.

The oxidative modification of low-density lipoproteins (LDL) is a key event in the formation of atheromatous lesions. Indeed, oxidized derivatives accumulate in the vascular wall and promote a local inflammatory process which triggers the progression of the atheromatous plaque. Myeloperoxidase (MPO) has been mentioned as a major contributor to this oxidative process.

Fibrinolysis and cardiovascular risk factors: association with fibrinogen, lipids, and monocyte count.

Background: Numerous risk factors for cardiovascular disease (CVD) have been determined by clinical epidemiological observations. The missing link could be related to endothelial dysfunction and the resulting hypofibrinolysis.

Methods: In this cross-sectional study, we evaluated 160 subjects (134 in primary prevention) characterized by their clinical cardiovascular risk factors (CVRF), i.

Thiol-containing molecules interact with the myeloperoxidase/H2O2/chloride system to inhibit LDL oxidation.

Oxidized low-density lipoproteins (LDL) accumulate in the vascular wall and promote a local inflammatory process contributing to the progression of atheromatous plaque. The key role of myeloperoxidase (MPO) in this process has been documented and the enzyme has been involved in the oxidative modification of apolipoprotein B-100 in the intima and at the surface of endothelial cells. As the inhibition of this last phenomenon could be of relevance in pharmacological interventions, thiol-containing molecules such as glutathione, captopril, and N-acetylcysteine (NAC) and its lysinate salt (NAL) were tested in this system and their properties were compared with those of flufenamic acid (control).