Skip to main content
Log in

TNF Revisited: Osteoprotegerin and TNF-related Molecules in Heart Failure

  • Pathophysiology: Neuroendocrine, Vascular, and Metabolic Factors (SD Katz, Section editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

The pathophysiological role of tumor necrosis factor (TNF) in myocardial failure has been extensively examined in experimental and clinical studies. Recent studies suggest that other members of the TNF/TNF receptor superfamily (TNFSF/TNFRSF) also may play a pathogenic role in chronic HF. TNF ligands, and in particular members of the TNFRSF, are expressed by a wide variety of cells, including myocardial cells. By activating the nuclear factor-κB (NF-κB) and death-related pathways, TNF ligands can induce a variety of effects within the myocardium, including apoptosis, hypertrophy, inflammation, and extracellular matrix remodeling. Among several TNFSF members that have been shown activated in HF, the OPG/RANK/RANKL (osteoprotegerin/receptor activator of NF-κB/RANK ligand) axis may be of importance in the pathogenesis of this disorder through different mechanisms. In this paper, we revisited the role of TNFSF/TNFRSF in the pathophysiology of HF, possibly representing new targets for therapy as well as new biomarkers in this disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–18.

    Article  PubMed  Google Scholar 

  2. Mann DL, Deswal A, Bozkurt B, Torre-Amione G. New therapeutics for chronic heart failure. Annu Rev Med. 2002;53:59–74.

    Article  PubMed  CAS  Google Scholar 

  3. Aukrust P, Ueland T, Muller F, et al. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation. 1998;97:1136–43.

    PubMed  CAS  Google Scholar 

  4. Aukrust P, Ueland T, Lien E, et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1999;83:376–82.

    Article  PubMed  CAS  Google Scholar 

  5. Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236–41.

    Article  PubMed  CAS  Google Scholar 

  6. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002;91:988–98.

    Article  PubMed  CAS  Google Scholar 

  7. Ware CF. The TNF superfamily. Cytokine Growth Factor Rev. 2003;14:181–4.

    Article  PubMed  CAS  Google Scholar 

  8. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745–56.

    Article  PubMed  CAS  Google Scholar 

  9. Dempsey PW, Doyle SE, He JQ, Cheng G. The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev. 2003;14:193–209.

    Article  PubMed  CAS  Google Scholar 

  10. Badorff C, Ruetten H, Mueller S, et al. Fas receptor signaling inhibits glycogen synthase kinase 3 beta and induces cardiac hypertrophy following pressure overload. J Clin Invest. 2002;109:373–81.

    PubMed  CAS  Google Scholar 

  11. Pan G, O’Rourke K, Chinnaiyan AM, et al. The receptor for the cytotoxic ligand TRAIL. Science. 1997;276:111–3.

    Article  PubMed  CAS  Google Scholar 

  12. Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation. 1996;93:704–11.

    PubMed  CAS  Google Scholar 

  13. Ueland T, Yndestad A, Oie E, et al. Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation. 2005;111:2461–8.

    Article  PubMed  CAS  Google Scholar 

  14. Herrera-Garza EH, Stetson SJ, Cubillos-Garzon A, et al. Tumor necrosis factor-alpha: a mediator of disease progression in the failing human heart. Chest. 1999;115:1170–4.

    Article  PubMed  CAS  Google Scholar 

  15. Chung JY, Park YC, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 2002;115:679–88.

    PubMed  CAS  Google Scholar 

  16. Gaur U, Aggarwal BB. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol. 2003;66:1403–8.

    Article  PubMed  CAS  Google Scholar 

  17. Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25:280–8.

    Article  PubMed  CAS  Google Scholar 

  18. Lutgens E, Lievens D, Beckers L, et al. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med. 2010;207:391–404.

    Article  PubMed  CAS  Google Scholar 

  19. Nishigaki K, Minatoguchi S, Seishima M, et al. Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in patients with chronic congestive heart failure. J Am Coll Cardiol. 1997;29:1214–20.

    Article  PubMed  CAS  Google Scholar 

  20. Yamaguchi S, Yamaoka M, Okuyama M et al.: Elevated circulating levels and cardiac secretion of soluble Fas ligand in patients with congestive heart failure. Am J Cardiol. 1999;83:1500–1503, A8.

    Google Scholar 

  21. Yndestad A, Damas JK, Geir EH, et al. Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure. Cardiovasc Res. 2002;54:175–82.

    Article  PubMed  CAS  Google Scholar 

  22. Schoppet M, Ruppert V, Hofbauer LC, et al. TNF-related apoptosis-inducing ligand and its decoy receptor osteoprotegerin in nonischemic dilated cardiomyopathy. Biochem Biophys Res Commun. 2005;338:1745–50.

    Article  PubMed  CAS  Google Scholar 

  23. Ueland T, Aukrust P, Yndestad A, et al. Soluble CD40 ligand in acute and chronic heart failure. Eur Heart J. 2005;26:1101–7.

    Article  PubMed  CAS  Google Scholar 

  24. Jeremias I, Kupatt C, Martin-Villalba A, et al. Involvement of CD95/Apo1/Fas in cell death after myocardial ischemia. Circulation. 2000;102:915–20.

    PubMed  CAS  Google Scholar 

  25. Madry C, Laabi Y, Callebaut I, et al. The characterization of murine BCMA gene defines it as a new member of the tumor necrosis factor receptor superfamily. Int Immunol. 1998;10:1693–702.

    Article  PubMed  CAS  Google Scholar 

  26. Kwon BS, Tan KB, Ni J, et al. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J Biol Chem. 1997;272:14272–6.

    Article  PubMed  CAS  Google Scholar 

  27. MacFarlane M, Ahmad M, Srinivasula SM, et al. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem. 1997;272:25417–20.

    Article  PubMed  CAS  Google Scholar 

  28. Pan G, Ni J, Yu G, et al. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Lett. 1998;424:41–5.

    Article  PubMed  CAS  Google Scholar 

  29. Pan G, Ni J, Wei YF, et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997;277:815–8.

    Article  PubMed  CAS  Google Scholar 

  30. Wilson EM, Diwan A, Spinale FG, Mann DL. Duality of innate stress responses in cardiac injury, repair, and remodeling. J Mol Cell Cardiol. 2004;37:801–11.

    Article  PubMed  CAS  Google Scholar 

  31. Bozkurt 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.

    PubMed  CAS  Google Scholar 

  32. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133–40.

    Article  PubMed  CAS  Google Scholar 

  33. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109:1594–602.

    Article  PubMed  CAS  Google Scholar 

  34. Heymans S, Hirsch E, Anker SD, et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2009;11:119–29.

    Article  PubMed  CAS  Google Scholar 

  35. Darnay BG, Aggarwal BB. Signal transduction by tumour necrosis factor and tumour necrosis factor related ligands and their receptors. Ann Rheum Dis. 1999;58 Suppl 1:I2–I13.

    Article  PubMed  CAS  Google Scholar 

  36. Kang PM, Izumo S. Apoptosis in heart: basic mechanisms and implications in cardiovascular diseases. Trends Mol Med. 2003;9:177–82.

    Article  PubMed  CAS  Google Scholar 

  37. Baines CP, Molkentin JD. STRESS signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol. 2005;38:47–62.

    Article  PubMed  CAS  Google Scholar 

  38. Linke A, Recchia F, Zhang X, Hintze TH. Acute and chronic endothelial dysfunction: implications for the development of heart failure. Heart Fail Rev. 2003;8:87–97.

    Article  PubMed  CAS  Google Scholar 

  39. Yndestad A, Holm AM, Muller F, et al. Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure. Cardiovasc Res. 2003;60:141–6.

    Article  PubMed  CAS  Google Scholar 

  40. Varda-Bloom N, Leor J, Ohad DG, et al. Cytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro. J Mol Cell Cardiol. 2000;32:2141–9.

    Article  PubMed  CAS  Google Scholar 

  41. Nitobe J, Yamaguchi S, Okuyama M, et al. Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes. Cardiovasc Res. 2003;57:119–28.

    Article  PubMed  CAS  Google Scholar 

  42. Yaniv G, Shilkrut M, Lotan R, et al. Hypoxia predisposes neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/Apo-1) receptor: Fas activation and apoptosis in hypoxic myocytes. Cardiovasc Res. 2002;54:611–23.

    Article  PubMed  CAS  Google Scholar 

  43. Almasan A, Ashkenazi A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 2003;14:337–48.

    Article  PubMed  CAS  Google Scholar 

  44. Baetu TM, Hiscott J. On the TRAIL to apoptosis. Cytokine Growth Factor Rev. 2002;13:199–207.

    Article  PubMed  CAS  Google Scholar 

  45. •• Hamid T, Gu Y, Ortines RV, et al. Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation. 2009;119:1386–97. This experimental study illustrates the complexity of the interplay between TNF-related molecules in HF by showing disparate and opposing effects by TNFR1 and TNFR2 on myocardial remodeling, hypertrophy, NF-κB activation, inflammation, and apoptosis.

    Article  PubMed  CAS  Google Scholar 

  46. Sivasubramanian N, Coker ML, Kurrelmeyer KM, et al. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation. 2001;104:826–31.

    Article  PubMed  CAS  Google Scholar 

  47. Nelson DP, Setser E, Hall DG, et al. Proinflammatory consequences of transgenic fas ligand expression in the heart. J Clin Invest. 2000;105:1199–208.

    Article  PubMed  CAS  Google Scholar 

  48. Li YY, Kadokami T, Wang P, et al. MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure. Am J Physiol Heart Circ Physiol. 2002;282:H983–9.

    PubMed  CAS  Google Scholar 

  49. Lee WH, Kim SH, Lee Y, et al. Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinases. Arterioscler Thromb Vasc Biol. 2001;21:2004–10.

    Article  PubMed  CAS  Google Scholar 

  50. Mach F, Schonbeck U, Fabunmi RP, et al. T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism: implications for tubule formation. Am J Pathol. 1999;154:229–38.

    Article  PubMed  CAS  Google Scholar 

  51. Yurovsky VV. Tumor necrosis factor-related apoptosis-inducing ligand enhances collagen production by human lung fibroblasts. Am J Respir Cell Mol Biol. 2003;28:225–31.

    Article  PubMed  CAS  Google Scholar 

  52. • Voloshenyuk TG, Hart AD, Khoutorova E, Gardner JD. TNF-alpha increases cardiac fibroblast lysyl oxidase expression through TGF-beta and PI3Kinase signaling pathways. Biochem Biophys Res Commun. 2011;413:370–5. This study illustrates the complex role of TNF-related molecules in ECM remodeling, promoting both matrix degradation and enhanced collagen synthesis partly depending on co-stimuli and concentration of TNF-related molecule.

    Article  PubMed  CAS  Google Scholar 

  53. Ueland T, Jemtland R, Godang K, et al. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol. 2004;44:1970–6.

    Article  PubMed  CAS  Google Scholar 

  54. Liu W, Feng W, Wang F, et al. Osteoprotegerin/RANK/RANKL axis in cardiac remodeling due to immuno-inflammatory myocardial disease. Exp Mol Pathol. 2008;84:213–7.

    Article  PubMed  CAS  Google Scholar 

  55. Ueland T, Aukrust P, Dahl CP, et al. Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis. J Intern Med. 2011;270:452–60.

    Article  PubMed  CAS  Google Scholar 

  56. Walsh MC, Choi Y. Biology of the TRANCE axis. Cytokine Growth Factor Rev. 2003;14:251–63.

    Article  PubMed  CAS  Google Scholar 

  57. Feng W, Li W, Liu W, et al. IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure. Exp Mol Pathol. 2009;87:212–8.

    Article  PubMed  CAS  Google Scholar 

  58. Sandberg WJ, Yndestad A, Oie E, et al. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol. 2006;26:857–63.

    Article  PubMed  CAS  Google Scholar 

  59. Halapas A, Zacharoulis A, Theocharis S, et al. Serum levels of the osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, metalloproteinase-1 (MMP-1) and tissue inhibitors of MMP-1 levels are increased in men 6 months after acute myocardial infarction. Clin Chem Lab Med. 2008;46:510–6.

    Article  PubMed  CAS  Google Scholar 

  60. • Niessner A, Hohensinner PJ, Rychli K, et al. Prognostic value of apoptosis markers in advanced heart failure patients. Eur Heart J. 2009;30:789–96. This study describes discrepant effects of soluble TNF-related markers of apoptosis on the prognosis of advanced HF and indicates that sTRAIL could be of interest as a therapeutic agent. It also illustrates the importance of fully understanding pathophysiological processes before selecting specific pathways as therapeutic target.

    Article  PubMed  CAS  Google Scholar 

  61. Secchiero P, Corallini F, Beltrami AP, et al. An imbalanced OPG/TRAIL ratio is associated to severe acute myocardial infarction. Atherosclerosis. 2010;210:274–7.

    Article  PubMed  CAS  Google Scholar 

  62. Corallini F, Secchiero P, Beltrami AP, et al. TNF-alpha modulates the migratory response of mesenchymal stem cells to TRAIL. Cell Mol Life Sci. 2010;67:1307–14.

    Article  PubMed  CAS  Google Scholar 

  63. Roysland R, Masson S, Omland T, et al. Prognostic value of osteoprotegerin in chronic heart failure: The GISSI-HF trial. Am Heart J. 2010;160:286–93.

    Article  PubMed  Google Scholar 

  64. Ueland T, Dahl CP, Kjekshus J, et al. Osteoprotegerin predicts progression of chronic heart failure: results from CORONA. Circ Heart Fail. 2011;4:145–52.

    Article  PubMed  CAS  Google Scholar 

  65. Bekker PJ, Holloway D, Nakanishi A, et al. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res. 2001;16:348–60.

    Article  PubMed  CAS  Google Scholar 

  66. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377:1276–87.

    Article  PubMed  CAS  Google Scholar 

  67. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358:2148–59.

    Article  PubMed  CAS  Google Scholar 

  68. Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardiovascular biomarkers. Circulation. 2007;115:949–52.

    Article  PubMed  Google Scholar 

  69. Rauchhaus M, Doehner W, Francis DP, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation. 2000;102:3060–7.

    PubMed  CAS  Google Scholar 

  70. Orus J, Roig E, Perez-Villa F, et al. Prognostic value of serum cytokines in patients with congestive heart failure. J Heart Lung Transplant. 2000;19:419–25.

    Article  PubMed  CAS  Google Scholar 

  71. Deswal A, Petersen NJ, Feldman AM, et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation. 2001;103:2055–9.

    PubMed  CAS  Google Scholar 

  72. Miettinen KH, Lassus J, Harjola VP, et al. Prognostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute decompensated heart failure. Eur J Heart Fail. 2008;10:396–403.

    Article  PubMed  CAS  Google Scholar 

  73. Valgimigli M, Ceconi C, Malagutti P, et al. Tumor necrosis factor-alpha receptor 1 is a major predictor of mortality and new-onset heart failure in patients with acute myocardial infarction: the Cytokine-Activation and Long-Term Prognosis in Myocardial Infarction (C-ALPHA) study. Circulation. 2005;111:863–70.

    Article  PubMed  CAS  Google Scholar 

  74. Rodriguez-Reyna TS, Arrieta O, Castillo-Martinez L, et al. Tumour Necrosis Factor alpha and Troponin T as predictors of poor prognosis in patients with stable heart failure. Clin Invest Med. 2005;28:23–9.

    PubMed  CAS  Google Scholar 

  75. Nappo F, Esposito K, Cioffi M, et al. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol. 2002;39:1145–50.

    Article  PubMed  CAS  Google Scholar 

  76. Petrovsky N, Harrison LC. The chronobiology of human cytokine production. Int Rev Immunol. 1998;16:635–49.

    Article  PubMed  CAS  Google Scholar 

  77. Chorianopoulos E, Rosenberg M, Zugck C, et al. Decreased soluble TWEAK levels predict an adverse prognosis in patients with chronic stable heart failure. Eur J Heart Fail. 2009;11:1050–6.

    Article  PubMed  CAS  Google Scholar 

  78. Richter B, Rychli K, Hohensinner PJ, et al. Differences in the predictive value of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in advanced ischemic and non-ischemic heart failure. Atherosclerosis. 2010;213:545–8.

    Article  PubMed  CAS  Google Scholar 

  79. Ferrari R, Bachetti T, Confortini R, et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation. 1995;92:1479–86.

    PubMed  CAS  Google Scholar 

  80. Ueland T, Kjekshus J, Froland SS, et al. Plasma levels of soluble tumor necrosis factor receptor type I during the acute phase following complicated myocardial infarction predicts survival in high-risk patients. J Am Coll Cardiol. 2005;46:2018–21.

    Article  PubMed  CAS  Google Scholar 

  81. Nybo M, Rasmussen LM. The capability of plasma osteoprotegerin as a predictor of cardiovascular disease: a systematic literature review. Eur J Endocrinol. 2008;159:603–8.

    Article  PubMed  CAS  Google Scholar 

  82. Omland T, Drazner MH, Ueland T, et al. Plasma osteoprotegerin levels in the general population: relation to indices of left ventricular structure and function. Hypertension. 2007;49:1392–8.

    Article  PubMed  CAS  Google Scholar 

  83. Omland T, Ueland T, Jansson AM, et al. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol. 2008;51:627–33.

    Article  PubMed  CAS  Google Scholar 

  84. Jellema A, Plat J, Mensink RP. Weight reduction, but not a moderate intake of fish oil, lowers concentrations of inflammatory markers and PAI-1 antigen in obese men during the fasting and postprandial state. Eur J Clin Invest. 2004;34:766–73.

    Article  PubMed  CAS  Google Scholar 

  85. Haack M, Pollmacher T, Mullington JM. Diurnal and sleep-wake dependent variations of soluble TNF- and IL-2 receptors in healthy volunteers. Brain Behav Immun. 2004;18:361–7.

    Article  PubMed  CAS  Google Scholar 

  86. Ueland T, Aukrust P, Damas JK, et al. The tumor necrosis factor superfamily in heart failure. Future Cardiol. 2006;2:101–11.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosures

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thor Ueland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ueland, T., Yndestad, A., Dahl, C.P. et al. TNF Revisited: Osteoprotegerin and TNF-related Molecules in Heart Failure. Curr Heart Fail Rep 9, 92–100 (2012). https://doi.org/10.1007/s11897-012-0088-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-012-0088-6

Keywords

Navigation