Enhanced TNFα and oxidative stress in patients with heart failure: effect of TNFα on platelet O₂ ^- production

Summary

Experimental studies have suggested that TNFα, 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 TNFα 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 car-diomyopathy (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 O₂ ^- production, and plasma TNFα.

In vivo results showed increased platelet O₂ ^- production and plasma TNFα levels in NYHA class III-IV compared with that in controls or in NYHA I-II (p<0,001); platelet O₂ ^- production correlated significantly (R=0,6; p<0,01) with TNFα plasma levels. In vitro studies showed TNFα dose-dependently (5-40 pg/ml) induced platelet O₂ ^- production, and that this effect was significantly inhibited by its specific inhibitor, WP9QY (1 μM); aspirin (100 μM), AACOCF₃, a specific PLA₂ inhibitor (14 μM), and DPI, an inhibitor of NADPH oxidase, significantly inhibited TNFα-mediated platelet O₂ ^- production.

This study suggests that in patients with heart failure, enhanced platelet O₂ ^- production is mediated by TNFα via activation of arachidonic acid and NADPH oxidase pathways.

Keywords

Platelets - heart failure - oxidative stress - TNF alpha

• References

• 1 Hensley K, Robinson KA, Gabbitta SP, Salsman S, Floyd R. Reactive oxygen species, cell signaling and cell injury. Free Rad Biol Med 2000; 28 (10) 1456-62.
• 2 Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82 (01) 47-95.
• 3 Violi F, Marino R, Milite MT, Loffredo L. Nitric oxide and its role in lipid peroxidation. Diab Met Res Rev 1999; 15: 283-8.
• 4 McIntyre M, Bohr DF, Dominiczak AF. Endothelial function in hypertension: the role of superoxide anion. Hypertension 1999; 34: 539-45.
• 5 Laursen JB, Somers M, Kurz S. et al. Endothelial regulation of vasomotion in apo-E deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 2001; 103: 1282-8.
• 6 Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxyni-trite. J Clin Invest 2002; 109: 817-26.
• 7 Ferrari R, Bachetti T, Agnoletti L, Comini L, Curello S. Endothelial function and dysfunction in heart failure. Eur Hearth J 1998; 19 suppl. G) G41-G47.
• 8 Wolin MS. Interactions of oxidants with vascular signaling systems. Arterioscler Thromb Vasc Biol 2000; 20: 1430-42.
• 9 Hink U, Li H, Mollnau H. et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001; 88: E14-22.
• 10 Halliwell B. Free radicals, antioxidant and human disease: curiosity, cause, or consequence. Lancet 1994; 344: 721-4.
• 11 Yasunari K, Maeda K, Nakamura M, Yoshikawa J. Oxidative stress in leukocytes is a possible link between blood pressure, blood glucose and C-reacting protein. Hypertension 2002; 39 (03) 777-80.
• 12 Gibson GE, Huang HM. Oxidative process in the brain and non-neuronal tissues as biomarkers of Alzheimer’s disease. Front Biosci 2002; 7: D1107-15.
• 13 Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001; 104: 2673-8.
• 14 Victor VM, Guayerbas N, De FM. Changes in the antioxidant content of mononuclear leucocytes from mice with endotoxin-induced oxidative stress. J Mol Cell Biochem 2002; 229: 107-11.
• 15 Hasper D, Hummel M, Kleber FX, Reindil I, Volk HD. Systemic inflammation in patients with heart failure. Eur Heart J 1998; 19: 761-5.
• 16 Tsutamoto T, Wada A, Matsumoto T. et al Relationship between Tumor Necrosis Factor alpha production and oxidative stress in the failing hearts of patients with dilated cardiomyopathy. JACC 2001; 37: 2086-92.
• 17 Yucel D, Aydogdu S, Cehreli S. et al. Increased oxidative stress in dilated cardiomyopathic heart failure. Clin Chem 1998; 44 (01) 148-54.
• 18 Ide T, Tsutsui H, Kinugawa S. et al. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 1999; 85: 357-63.
• 19 Feldman AM, Combes A, Wagner D. et al. The role of Tumor Necrosis Factor in the pathophysiology of heart failure. JACC 2000; 35 (03) 537-43.
• 20 Aukrust P, Ueland T, Lien E. et al. Cytokine network in congestive heart failure secondary to ischaemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999; 83: 376-82.
• 21 Hare JM. Oxidative stress and apoptosis in heart failure. Circ Res 2001; 89: 198-200.
• 22 Saavedra WF, Paolocci N, St John ME. et al. Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. Circ Res 2002; 90: 297-304.
• 23 Iuliano L, Colavita R, Leo R, Praticò D, Violi F. Oxygen free radicals and platelet function. Free Radic Biol Med 1997; 22: 999-1006.
• 24 Pignatelli P, Pulcinelli FM, Lenti L, Gazzaniga PP, Violi F. Vitamin E inhibits collagen-induced platelet activation by blunting hydrogen peroxide. Arterioscler Tromb Vasc Biol 1999; 91: 2542-7.
• 25 Brandenburg RO, Chazov D, Cherian G. et al. Report of the WHO/IFSC Task Force on the definition and classification of cardiomyopathies. Circulation 1981; 64: 437-8.
• 26 Pignatelli P, Pulcinelli FM, Lenti L, Gazzaniga PP, Violi F. Hydrogen Peroxide is involved in collagen-induced platelet activation. Blood 1998; 91 (02) 484-90.
• 27 Caldefie-Chezet F, Walrand S, Moinard C, Tridon A, Chassagne J, Vasson MP. Is the neu-trophil reactive oxygen species production measured by luminol and lucigenin chemiluminescence intra or extracellular? Comparison with DCFH-DA flow cytometry and cytochrome c reduction. Clin Chim Acta 2002; 319: 9-17.
• 28 Freedman JE, Keaney JF. Nitric Oxide and superoxide detection in human platelet. Method Enzymol 1999; 301: 61-70.
• 29 Liochev SI, Fridovich I. Lucigenin (Bis-N-methylacridinium) as a mediator of superoxide anion production. Arch Biochem Bioph 1997; 337 (01) 115-20.
• 30 Afans’ev IB, Ostrachovitch EA, Korkina LG. Lucigenin is a mediator of cytochrome C reduction but not of superoxide anion production. Arch Biochem Biophys 1999; 366 (02) 267-74.
• 31 Vasquez-Vivar J, Hogg NH, Pritchard Jr. A.. Superoxide anion formation from lucigenin: an electron spin resonance spin-trapping study. FEBS letters 1997; 403: 127-30.
• 32 Leo R, Praticò D, Iuliano L. et al. Platelet activation by superoxide anion and hydroxyl radicals intrinsically generated by platelets that undergone anoxia and then reoxygenated. Circulation 1997; 95: 885-91.
• 33 Rothe G, Valet G. Flow cytometrical analisys of respiratory burst activity in phagocytes with hydroetidine and 2,7-dicloroflorescin. J Leukoc Biol 1990; 47: 440-8.
• 34 Limb GA, Webster L, Soomro H, Janikoun S, Shilling J. Platelet expression of tumor necrosis factor-alpha (TNFα), TNF receptors and intracellular adhesion molecule-1 (ICAM-1) in patients with proliferative diabetic retinopathy. Clin Exp Immunol 1999; 118: 213-8.
• 35 Dimmeler S, Zeiher AM. Reactive oxygen species and vascular cell apoptosis in response to Angiotensin II and pro-atherosclerotic factors. Reg Peptides 2000; 90: 19-25.
• 36 Khaper N, Singal PK. Modulation of oxidative stress by a selective inhibition of Angiotensin II type 1 receptors in MI Rats. JACC 2001; 37 (05) 1461-6.
• 37 Zhao S-P., Xu T-D. Elevated Tumor Necrosis Factor alpha of blood mononuclear cells in patients with congestive heart failure. Int J Cardiol 1999; 17: 257-61.
• 38 Meldrum DR. Tumor Necrosis Factor in the heart. Am J Physiol 1998; 274: R577-R595.
• 39 Torre-Amione G, Kapadia S, Lee J. et al. Tumor Necrosis Factor-alpha and Tumor Necrosis Factor receptors in the failing human heart. Circulation 1997; 12: 218-23.
• 40 Bozzkurt B, Torre-Amione G, Warren MS. et al. Results of targeted anti Tumor Necrosis Factor therapy with Etanercept (ENBREL) in patients with advanced heart failure. Circulation 2001; 103: 1044-7.
• 41 Sharma R, Coats A, Anker S. The role of inflammatory mediators in chronic heart failure: cytokines, nitric oxide and endothelin-1. Int J Cardiol 2000; 72: 175-86.
• 42 Kelly RA, Smith TW. Cytokines and cardiac contractile function. Circulation 1996; 95: 778-81.
• 43 Song W, Lu X, Feng Q. Tumor Necrosis Factor-alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocites. Cardiovasc Res 2000; 45: 595-602.
• 44 Corda S, Laplace C, Vicaut E, Duranteau J. Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol 2001; 24: 762-8.
• 45 Suematsu N, Tsutsui H, Wen J. et al. Oxidative stress mediates Tumor Necrosis Factor-α–induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003; 107: 1418-23.
• 46 Seno T, Inoue N, Gao D. et al. Involvement of NADH/NADPH oxidase in human platelet ROS production. Thromb Res 2001; 103: 399-409.
• 47 Sanguigni V, Pignatelli P, Caccese D. et al. Increased superoxide anion production by platelets in hypercholesterolemic patients. Thromb Haemost 2002; 87 (05) 796-801.