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The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.

Thgoal of this study was to evaluate the efficacy of the antioxidant olive constituent, oleuropein, on infarct size, oxidative damage, and the metabolic profile in rabbits subjected to ischemia. Oleuropein, 10 or 20 mg/(kg x d), was administered to 8 groups that consumed a normal or hypercholesterolemic diet for 6 wk or only the higher dose for 3 wk. Circulating levels of malondialdehyde, protein carbonyl, nitrite+nitrate, cholesterol, triglycerides, SOD activity, and the metabolic profile were measured using 1H NMR spectra. In rabbits that consumed the normal diet, the infarct size (percentage of infarct to risk areas) was reduced by the administration of 10 mg oleuropein/(kg x d) (16.1 +/- 2.9%) or 20 mg oleuropein/(kg x d) for 3 wk (21.7 +/- 2.2%) or for 6 wk (24.3 +/- 1.3%) compared with the control group (48.05 +/- 2.0%, P < 0.05). Only the higher dose of 20 mg/(kg x d) reduced the infarct size in hypercholesterolemic rabbits (34.7 +/- 4.4% for 6 wk and 34.8 +/- 6.1% for 3 wk) compared with the cholesterol-fed control group (52.8 +/- 2.4%, P < 0.05). Oleuropein decreased the plasma lipid peroxidation product and protein carbonyl concentrations compared with the control groups, in which these factors increased relative to baseline due to ischemia and reperfusion. Furthermore, in rabbits administered oleuropein, RBC superoxide dismutase activity did not change during ischemia and reperfusion. This activity was significantly higher than in both control groups in which it was reduced by ischemia and reperfusion compared with baseline. Treatment for 6 wk with both doses of oleuropein reduced total cholesterol and triglyceride concentrations. 1H NMR spectra revealed a different profile of glycolysis metabolites in the oleuropein-treated groups compared with the controls. Oleuropein, for 3 or 6 wk, reduced the infarct size, conferred strong antioxidant protection and reduced the circulating lipids. This is the first experimental study in vivo that suggests the possibility of using an olive constituent in the treatment of ischemia.

Background-Interleukin-1 increases nitrooxidative stress. We investigated the effects of a human recombinant interleukin-1a receptor antagonist (anakinra) on nitrooxidative stress and vascular and left ventricular function. Methods and Results-In an acute, double-blind trial, 23 patients with rheumatoid arthritis were randomized to receive a single injection of anakinra (150 mg SC) or placebo and, after 48 hours, the alternative treatment. At baseline and 3 hours after the injection, we assessed (1) coronary flow reserve, aortic distensibility, systolic and diastolic (Em) velocity of the mitral annulus, and E to Em ratio (E/Em) using echocardiography; (2) flow-mediated, endothelium-dependent dilation of the brachial artery; and (3) malondialdehyde, nitrotyrosine, interleukin-6, endothelin-1, and C-reactive protein.In a chronic, nonrandomized trial, 23 patients received anakinra and 19 received prednisolone for 30 days, after which all indices were reassessed. Compared with baseline, there was a greater reduction in malondialdehyde, nitrotyrosine, interleukin-6, and endothelin-1 and a greater increase in flow-mediated dilation, coronary flow reserve, aortic distensibility, systolic velocity of mitral annulus, and E/Em after anakinra than after placebo (malondialdehyde Ϫ25% versus 9%; nitrotyrosine Ϫ38% versus Ϫ11%; interleukin-6 Ϫ29% versus 0.9%; endothelin-1 Ϫ36% versus Ϫ11%; flow-mediated dilation 45% versus Ϫ9%; coronary flow reserve 29% versus 4%; and aortic distensibility 45% versus 2%; PϽ0.05 for all comparisons). After 30 days of treatment, the improvement in biomarkers and in vascular and left ventricular function was greater in the anakinra group than in the prednisolone group (PϽ0.05). Conclusions

Ischaemic heart disease is one of the leading causes of morbidity and mortality worldwide. The development of cardioprotective therapeutic agents remains a partly unmet need and a challenge for both medicine and industry, with significant financial and social implications. Protection of the myocardium can be achieved by mechanical vascular occlusions such as preconditioning (PC), when brief episodes of ischaemia/reperfusion (I/R) are experienced prior to ischaemia; postconditioning (PostC), when the brief episodes are experienced at the immediate onset of reperfusion; and remote conditioning (RC), when the brief episodes are experienced in another vascular territory. The elucidation of the signalling pathways, which underlie the protective effects of PC, PostC and RC, would be expected to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent reperfusion injury. Gasotransmitters including NO, hydrogen sulphide (H2S) and carbon monoxide (CO) are a growing family of regulatory molecules that affect physiological and pathological functions. NO, H2S and CO share several common properties; they are beneficial at low concentrations but hazardous in higher amounts; they relax smooth muscle cells, inhibit apoptosis and exert anti-inflammatory effects. In the cardiovascular system, NO, H2S and CO induce vasorelaxation and promote cardioprotection. In this review article, we summarize current knowledge on the role of the gasotransmitters NO, H2S and CO in myocardial I/R injury and cardioprotection provided by conditioning strategies and highlight future perspectives in cardioprotection by NO, H2S, CO, as well as their donor molecules. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx. Abbreviations 3MP, 3-mercaptopyruvate; 3-MST, 3-mercaptopyruvate transferase; BCA, cyano-L-alanine; CBS, cystathionine β-synthase; CHD, coronary heart disease; CK, creatinine kinase; CORM, carbon monoxide-releasing molecule; CSE, cystathionine γ-lyase; CyPD, cyclophilin D; HPDTT, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione; eNOS, endothelial nitric oxide synthase; FeTPPS, 5,10,15, porphyrinato iron; GYY4137, morpholin-4-ium 4-methoxyphenyl-morpholino-phosphinodithioate; HNO, nitroxyl; HO, haem oxygenase; I/R, ischaemia/reperfusion; iNOS, inducible nitric oxide synthase; L-NAME, N-nitro-L-arginine methylester; L-NNA, Nω-nitro-l-arginine; LV, left ventricular; MitoSNO, mitochondria-targeted S-nitrosothiols; mPTP, mitochondria permeability transition pore; nNOS, neuronal nitric oxide synthase; Nrf2, nuclear factor (erythroid-derived 2)-like 2; NSAIDs, non-steroidal antiinflammatory drugs; ONOO − , peroxynitrite; PRG, DL-propargylglycine; PC, preconditioning; PostC, postconditioning; RC, remote conditioning; RISK, reperfusion injury salvage kinase; ROS, reactive oxygen species; SAC, S-allylcysteine; SAFE, survivor activating factor enhancement; SOD, superoxide dismutase; XOR, xanthin...

Background— We investigated the effects of anakinra, an interleukin-1 receptor antagonist, on coronary and left ventricular function in coronary artery disease (CAD) patients with rheumatoid arthritis. Methods and Results— In a double-blind crossover trial, 80 patients with rheumatoid arthritis (60 with CAD and 20 without) were randomized to a single injection of anakinra or placebo and after 48 hours to the alternative treatment. At baseline and 3 hours after treatment, we assessed (1) flow-mediated dilation of brachial artery; (2) coronary flow reserve, ejection fraction, systemic arterial compliance, and resistance by echocardiography; (3) left ventricular global longitudinal and circumferential strain, peak twisting, untwisting velocity by speckle tracking; and (4) interleukin-1β, nitrotyrosine, malondialdehyde, protein carbonyl, and Fas/Fas ligand levels. At baseline, patients with CAD had 3-fold higher interleukin-1β, protein carbonyl, higher nitrotyrosine, malondialdehyde, and Fas/Fas ligand than non-CAD ( P <0.05). After anakinra, there was a greater improvement of flow-mediated dilation (57±4% versus 47±5%), coronary flow reserve (37±4% versus 29±2%), arterial compliance (20±18% versus 2±17%), resistance (−11±19% versus 9±21%), longitudinal strain (33±5% versus 18±2%), circumferential strain (22±5% versus 13±5%), peak twisting (30±5% versus 12±5%), untwisting velocity (23±5% versus 13±5%), ejection fraction (12±5% versus 0.5±5%), apoptotic and oxidative markers, and, in particular, of protein carbonyl (35±20% versus 14±9%) in CAD than in non-CAD patients ( P <0.01). No changes in the examined markers were observed after placebo. Conclusions— Interleukin-1 inhibition causes a greater improvement in endothelial, coronary aortic function in addition to left ventricular myocardial deformation and twisting in rheumatoid arthritis patients with CAD than in those without. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01566201.

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