Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Derived Superoxide and Vascular Endothelial Dysfunction in Human Heart Failure

• Published in: Journal of the American College of Cardiology Vol. 51; no. 14; pp. 1349 - 1356
• Main Authors: Dworakowski, Rafał, Walker, Simon, Momin, Aziz, Desai, Jatin, El-Gamel, Ahmed, Wendler, Olaf, Kearney, Mark T., Shah, Ajay M.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 08.04.2008; Elsevier Science; Elsevier Limited
• Subjects: Aged; Atherosclerosis; Biological and medical sciences; Biomarkers - metabolism; Blood pressure; C-Reactive Protein - metabolism; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - physiopathology; Case-Control Studies; Coronary vessels; Diabetes; Endothelium; Endothelium, Vascular - physiopathology; Exercise Tolerance; Female; Heart; Heart attacks; Heart failure; Heart Failure - metabolism; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Hypertension; Inflammation - metabolism; Internal Medicine; Male; Medical sciences; Middle Aged; NADPH Oxidases - metabolism; Nitrous Oxide - metabolism; Oxidative Stress; Reactive Oxygen Species - metabolism; Regression analysis; Rodents; Saphenous Vein; Studies; Superoxides - metabolism; Thermal cycling; CHF; CRP; NADPH; EF; NO; IL; LV; TNF; NOS; SNP; Nox; ROS; CABG; DPI; C-reactive protein; ejection fraction; nicotinamide adenine dinucleotide phosphate oxidase(s); chronic heart failure; sodium nitroprusside; reactive oxygen species; left ventricle/ventricular; nitric oxide synthase; interleukin; nitric oxide; diphenyleneiodonium; nicotinamide adenine dinucleotide phosphate; coronary artery bypass graft; tumor necrosis factor; Human; Heart failure; Phosphates; Enzyme; Dinucleotide; Oxidase; Adenine; Cardiovascular disease; Endothelium; Hyperoxides; Dysfunction; Heart disease; Blood vessel; Endothelial dysfunction; Nicotinamide; Oxidoreductases; Circulatory system; Cardiology
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2007.12.033

Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Derived Superoxide and Vascular Endothelial Dysfunction in Human Heart Failure Rafał Dworakowski, Simon Walker, Aziz Momin, Jatin Desai, Ahmed El-Gamel, Olaf Wendler, Mark T. Kearney, Ajay M. Shah Endothelial dysfunction secondary to increased degradation of nitric oxide by reactive oxygen species (ROS) contributes to dysregulation of vascular tone in human heart failure. We investigated the role of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) in patients with heart failure. Endothelial dysfunction in saphenous vein segments was associated with increased Nox expression, superoxide generation, and elevated C-reactive protein levels. Inflammatory mechanisms may underlie the increased ROS generation. We investigated the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in endothelial dysfunction in human heart failure. Vascular endothelial dysfunction in human heart failure contributes to increased tone, exercise limitation, and dysregulation of venous capacitance and vascular volume. The NADPH oxidases (Nox) are an important source of oxidative stress, but their role in the endothelial dysfunction of human heart failure remains unknown. Endothelium-dependent and -independent vasorelaxation were assessed in saphenous vein segments obtained from consecutive patients with heart failure (n = 19) or normal left ventricular function (control; n = 35) undergoing coronary artery bypass graft. Saphenous vein superoxide production was measured by lucigenin-enhanced chemiluminescence and messenger ribonucleic acid expression of relevant transcripts quantified by real-time polymerase chain reaction. Heart failure patients had significantly worse endothelial function than control subjects (15.2 ± 3% vs. 40.5 ± 8.4% relative relaxation; p < 0.05), elevated C-reactive protein (CRP) levels (8.6 ± 2.7 mg/l vs. 2.6 ± 0.4 mg/l; p < 0.05), over 2-fold higher NADPH-dependent superoxide generation (p < 0.05), and significantly higher expression of the Nox4 isoform and regulatory subunit p67phox. Superoxide levels were positively correlated with New York Heart Association functional class (r = 0.684; p < 0.05) and CRP (r = 0.501; p < 0.005; n = 32). Venous endothelial dysfunction in human heart failure is associated with increased Nox-derived superoxide generation. Inflammatory mechanisms may be involved in the increased reactive oxygen species generation.