Enhanced TNF alpha and oxidative stress in patients with heart failure: effect of TNF alpha on platelet O2- production.
Experimental studies have suggested that TNF alpha, a pro-inflammatory cytokine, may contribute to the deterioration of cardiovascular function through various mechanisms, including the generation of reactive oxygen species. It has not yet been demonstrated whether TNF alpha has prooxidant activity in patients with heart failure, and what the mechanism eventually resulting in this effect are. We analyzed 42 patients (38 men and 4 women, aged 26 to 74 years) with heart failure, secondary to idiopathic dilated cardiomyopathy (n=21), coronary artery disease (n=15), and valve disease (n=6), and 20 controls (18 men and 2 women, aged 49 to 67 years). Ten patients were in class I, 9 in class II, 15 in class III and 8 in class IV according to NYHA Classification. Blood samples were obtained from each patient to evaluate basal and collagen-induced platelet O(2)(-) production, and plasma TNF alpha. In vivo results showed increased platelet O(2)(-) production and plasma TNF alpha levels in NYHA class III-IV compared with that in controls or in NYHA I-II (p<0,001); platelet O(2)(-) production correlated significantly (R=0,6; p<0,01) with TNF alpha plasma levels. In vitro studies showed TNF alpha dose-dependently (5-40 pg/ml) induced platelet O(2)(-) production, and that this effect was significantly inhibited by its specific inhibitor, WP9QY (1 microM); aspirin (100 microM), AACOCF(3), a specific PLA(2) inhibitor (14 microM), and DPI, an inhibitor of NADPH oxidase, significantly inhibited TNF alpha-mediated platelet O(2)(-) production. This study suggests that in patients with heart failure, enhanced platelet O(2)(-) production is mediated by TNF alpha via activation of arachidonic acid and NADPH oxidase pathways.
De Biase
Luciano
L
Cardiologia, Ospedale Sant' Andrea, II Facoltà di Medicina e Chirurgia, Università La Sapienza di Roma, Rome, Italy.
Pignatelli
Pasquale
P
Lenti
Luisa
L
Tocci
Giuliano
G
Piccioni
Fabiana
F
Riondino
Silvia
S
Pulcinelli
Fabio M
FM
Rubattu
Speranza
S
Volpe
Massimo
M
Violi
Francesco
F
D000328:Adult; D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000378:metabolism*; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000502:physiology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*
D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D019255:NADPH Oxidases