3-nitrotyrosine and Coronary-Disease

The effect of reactive oxygen species (ROS) on platelet function in coronary heart disease (CHD) is complex and poorly defined. Platelet aggregation studies in healthy volunteers have demonstrated contrasting results when platelets are exposed to ROS. We investigated the effect of ROS on whole blood aggregation (WBA) and the endothelial cell-platelet interaction in patients with CHD.. ROS generated by xanthine and xanthine oxidase caused a concentration-dependent inhibition of WBA in blood from healthy donors and patients with CHD. In patients with CHD, 100 μM xanthine and 100 mU/ml xanthine oxidase inhibited WBA in response to 3 μg/ml collagen by 28.9% (95% CI 15.9%-41.8%, p<0.001) and in response to 5 μM ADP by 36.0% (95% CI 9.6%-62.4%, p=0.005). Using nitrotyrosine expression, platelets isolated from patients with CHD were found to be susceptible to peroxynitrite damage. The addition of 1 × 10(5) cultured endothelial cells inhibited WBA in response to 3 μg/ml collagen by 31.2% (95% CI 12.2%-50.2%, p<0.05) and in response to 5 μM ADP by 31.6% (95% CI 2.5-60.7%, p<0.05). Addition of xanthine and xanthine oxidase did not alter this effect, however pre-treatment of endothelial cells with a nitric oxide synthase inhibitor (L-NAME) partly reversed the inhibition.. ROS inhibit WBA in blood from patients with CHD. Whilst endothelial cells also inhibit WBA, the effect is attenuated by L-NAME, suggesting that nitric oxide is likely to remain an important protective mechanism against thrombosis in CHD.

Topics: Aged; Blood Platelets; Cell Communication; Coronary Disease; Endothelial Cells; Endothelium, Vascular; Enzyme Inhibitors; Female; Hemostasis; Humans; Male; Middle Aged; NG-Nitroarginine Methyl Ester; Platelet Aggregation; Reactive Oxygen Species; Tyrosine; Xanthine; Xanthine Oxidase

Exposure to fine particulate air pollution is associated with increased cardiovascular morbidity and mortality. We previously demonstrated that exposure to dilute diesel exhaust causes vascular dysfunction in humans.. We conducted a study to determine whether exposure to ambient particulate matter causes vascular dysfunction.. Twelve male patients with stable coronary heart disease and 12 age-matched volunteers were exposed to concentrated ambient fine and ultrafine particles (CAPs) or filtered air for 2 hr using a randomized, double-blind cross-over study design. We measured peripheral vascular vasomotor and fibrinolytic function, and inflammatory variables-including circulating leukocytes, serum C-reactive protein, and exhaled breath 8-isoprostane and nitrotyrosine-6-8 hr after both exposures.. Particulate concentrations (mean +/- SE) in the exposure chamber (190+/-37 microg/m(3)) were higher than ambient levels (31+/-8 microg/m(3)) and levels in filtered air (0.5+/-0.4 microg/m(3); p<0.001). Chemical analysis of CAPs identified low levels of elemental carbon. Exhaled breath 8-isoprostane concentrations increased after exposure to CAPs (16.9+/-8.5 vs. 4.9+/-1.2 pg/mL, p<0.05), but markers of systemic inflammation were largely unchanged. Although there was a dose-dependent increase in blood flow and plasma tissue plasminogen activator release (p<0.001 for all), CAPs exposure had no effect on vascular function in either group.. Despite achieving marked increases in particulate matter, exposure to CAPs--low in combustion-derived particles--did not affect vasomotor or fibrinolytic function in either middle-aged healthy volunteers or patients with coronary heart disease. These findings contrast with previous exposures to dilute diesel exhaust and highlight the importance of particle composition in determining the vascular effects of particulate matter in humans.

Topics: C-Reactive Protein; Cardiovascular System; Coronary Disease; Cross-Over Studies; Dinoprost; Double-Blind Method; Fibrinolysis; Humans; Inhalation Exposure; Male; Middle Aged; Particulate Matter; Tyrosine; Vasomotor System

Patients with heart disease are frequently treated with supplemental oxygen. Although oxygen can exhibit vasoactive properties in many vascular beds, its effects on the coronary circulation have not been fully characterized. To examine whether supplemental oxygen administration affects coronary blood flow (CBF) in a clinical setting, we measured in 18 patients with stable coronary heart disease the effects of breathing 100% oxygen by face mask for 15 min on CBF (via coronary Doppler flow wire), conduit coronary diameter, CBF response to intracoronary infusion of the endothelium-dependent dilator ACh and to the endothelium-independent dilator adenosine, as well as arterial and coronary venous concentrations of the nitric oxide (NO) metabolites nitrotyrosine, NO(2)(-), and NO(3)(-). Relative to breathing room air, breathing of 100% oxygen increased coronary resistance by approximately 40%, decreased CBF by approximately 30%, increased the appearance of nitrotyrosine in coronary venous plasma, and significantly blunted the CBF response to ACh. Oxygen breathing elicited these changes without affecting the diameter of large-conduit coronary arteries, coronary venous concentrations of NO(2)(-) and NO(3)(-), or the coronary vasodilator response to adenosine. Administering supplemental oxygen to patients undergoing cardiac catheterization substantially increases coronary vascular resistance by a mechanism that may involve oxidative quenching of NO within the coronary microcirculation.

Topics: Acetylcholine; Adenosine; Adult; Aged; Cardiac Catheterization; Coronary Circulation; Coronary Disease; Drug Interactions; Endothelin-1; Female; Humans; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Oxygen; Tyrosine; Vasodilator Agents

We aimed to analyze the association of nitrotyrosine (N-TYR) levels and long-term survival in an ongoing coronary heart disease (CHD) prospective cohort, the Acute Coronary Syndrome Registry Strategy (ERICO study).. N-TYR levels collected during acute and subacute phase from onset of acute coronary syndrome (ACS) symptoms (myocardial infarction and unstable angina) were evaluated in 342 patients. We calculated case-fatality rates (180-days, 1 year, 2 years and 4 years) and survival analyses up to 4 years using Kaplan-Meier curves and Cox regression with respective cumulative hazard ratios (95% confidence interval; 95%CI), according to N-TYR tertiles up to 4 years of follow-up. Models are presented as crude, age and sex-adjusted and further adjusted for lipids and other confounders.. Overall, median level of N-TYR was 208.33 nmol/l (range: 3.09 to 1500 nmol/l), regardless ACS subtype. During follow-up of 4 years, we observed 44 (12.9%) deaths. Overall survival rate was 298 (87.1%) (Survival days: 1353, 95%CI: 1320-1387 days). N-TYR levels did not associate with mortality / survival rates up to 4 years.. No relationship was found between N-TYR levels and mortality rates after ACS during 4-year follow-up in the ERICO study.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Coronary Disease; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors; Survival Rate; Time Factors; Tyrosine

The CD40-CD40L system has been implicated in the pathogenesis of atherothrombotic complications in cardiovascular disease. The aim of this study was to determine the relationship between plasma soluble CD40 ligand (sCD40L) and symptomatic coronary heart disease (CHD) in end-stage renal disease (ESRD) patients on maintenance haemodialysis (HD).. This cross-sectional study included 57 HD patients, 31 of whom had symptomatic CHD. Lipid profile, markers of endothelial activation such as sCD40L, and both inflammatory and oxidative stress markers were measured and analyzed.. The sCD40L concentration was significantly higher in HD patients than in controls (1.34 +/- 0.53 vs 0.86 +/- 0.12 ng/mL, P < 0.01). Plasma concentration of sCD40L (P < 0.01), soluble vascular adhesion molecule-1 (sVCAM-1; P < 0.01) and high-sensitivity CRP (hsCRP; P < 0.01) were higher in HD patients with symptomatic CHD than in those without CHD. In addition, we also found that oxidative stress biomarkers such as nitrotyrosine (NT), malonaldehyde (MDA) and protein carbonyl (PC) were significantly elevated in patients with symptomatic CHD compared to those without. There was a strong overall positive relationship between sCD40L concentration and sVCAM-1 (r = 0.54, P < 0.001), MDA (r = 0.365, P < 0.01), NT (r = 0.293, r < 0.05) and log-transformed triglycerides (r = 0.275, P < 0.05).. Circulating concentrations of sCD40L were elevated in HD patients with symptomatic CHD. This study suggests that CD40-CD40L may play a potentially important role in the atherosclerotic complications of HD patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Case-Control Studies; CD40 Ligand; Coronary Disease; Cross-Sectional Studies; Female; Humans; Inflammation Mediators; Kidney Failure, Chronic; Lipids; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pilot Projects; Protein Carbonylation; Renal Dialysis; Tyrosine; Up-Regulation; Vascular Cell Adhesion Molecule-1

Myocardial hibernation may result from repetitive episodes of transient ischaemia leading to prolonged dysfunction. Inducible nitric oxide synthase (iNOS) expression has been demonstrated in animals following brief, non-lethal ischaemia-reperfusion injury. We therefore, hypothesised that in human hibernating myocardium: 1). iNOS would be present; 2). the reaction of nitric oxide and superoxide would form the strong oxidant peroxynitrite; 3) that this process would be accompanied by the expression of cyclooxygenase-2 (Cox-2) which interacts with NOS and whose products could further affect myocardial function.. In sixteen patients with coronary artery disease (CAD), left ventricular biopsies were obtained from chronically dysfunctional segments subtended by a stenotic artery (> 75 %) and shown to be viable by (18)F-fluorodeoxyglucose positron emission tomography. Comparison was made with myocardial biopsies (n = 8) from normally contracting myocardium in patients undergoing coronary surgery, from unused transplant donors and at post-mortem. Regional wall motion score improved in all patients 6 months post-revascularisation (from 2.7 +/- 0.7 to 1.5 +/- 0.5; p < 0.001), confirming hibernation. Immunocytochemistry localized reactivity to iNOS, Cox-2 and nitrotyrosine (a marker of peroxynitrite formation) to cardiomyocytes from hibernating segments. No difference in reactivity to endothelial NOS was seen between hibernating and control cardiomyocytes.. Cox-2 and iNOS are co-expressed in hibernating myocardium with nitrotyrosine suggesting nitric oxide production and peroxynitrite formation. We propose that this is secondary to ischaemia-reperfusion and that the products of these enzymes may have consequences for myocardial contractile function and survival.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biopsy; Coronary Disease; Cyclooxygenase 2; Diuretics; Echocardiography; Humans; Immunohistochemistry; Isoenzymes; Membrane Proteins; Middle Aged; Myocardial Stunning; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Tyrosine

The inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide in response to cytokine stimulation. Previous investigations have demonstrated iNOS expression in the setting of acute and chronic rejection in experimental cardiac transplant models. The goal of this study was to investigate whether iNOS is upregulated in human transplant coronary artery disease (TCAD), a major cause of late mortality after cardiac transplantation.. We studied 15 patients with TCAD and 10 with normal coronary arteries. In situ hybridization and immunohistochemistry were used in tissue sections to localize iNOS mRNA and protein, respectively. The presence of peroxynitrite was indirectly assessed by immunostaining with an anti-nitrotyrosine antibody. Normal coronary arteries had no evidence of iNOS expression. In contrast, 30 of 36 coronary artery segments with TCAD (83%) were immunostained by the iNOS antibody. The presence of iNOS mRNA was demonstrated in these vessels by in situ hybridization. Specific cell markers identified iNOS-positive cells as neointimal macrophages and smooth muscle cells. Nitrotyrosine immunoreactivity colocalized with iNOS expression in arteries with TCAD, distributed in macrophages and smooth muscle cells.. iNOS mRNA and protein are expressed in human arteries with TCAD, where they are associated with extensive nitration of protein tyrosines. These findings indicate that the high-output nitric oxide pathway and possibly the oxidant peroxynitrite might be involved in the process leading to the development of TCAD.

Topics: Adult; Child; Child, Preschool; Coronary Artery Disease; Coronary Disease; Coronary Vessels; Endothelium, Vascular; Female; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic; Heart Transplantation; Humans; In Situ Hybridization; Macrophages; Male; Middle Aged; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; RNA, Messenger; Tyrosine