Skip to main content
SpringerLink
Log in

Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy

  • ORIGINAL CONTRIBUTION
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

To investigate the effect of anti-cytokine-based therapy in the course of diabetic cardiomyopathy, we performed a study using an anti-TNF-α monoclonal antibody treatment (mab) in Sprague male Dawley (SD) rats with streptozotocin-induced diabetic cardiomyopathy. Five days after streptozotocin injection, rats were treated with the anti-TNF-α mAb C432A for 6 weeks.At the end of the study, left ventricular (LV) function was determined by a pressure-catheter. Intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, β2-lymphocyte-integrins+ (CD18+, CD11a+, CD11b+), ED1/CD68+ and cytokine (TNF-α, interleukin (IL)-1β)- expressing infiltrates, total collagen content and stainings of collagen I and III were quantified by digital image analysis. LV phosphorylated and total ERK protein levels were determined by Western Blot. TNFα-antagonism reduced ICAM-1- and VCAM-1 expression and leukocyte infiltration to levels of non-diabetics and decreased macrophage residence by 3.3-fold compared with untreated diabetics. In addition, anti-TNF-α mAb-treatment decreased diabetes-induced cardiac TNF-α and IL-1β expression by 2.0-fold and 1.8- fold, respectively, and reduced the ratio of phosphorylated to total ERK by 2.7-fold. The reduction in intramyocardial inflammation was associated with a 5.4-fold and 3.6-fold reduction in cardiac collagen I and III content, respectively. This was reflected by a normalization of cardiac total collagen content to levels of non-diabetics and associated with an improved LV function. TNFα-antagonism attenuates the development of experimental diabetic cardiomyopathy associated with a reduction of intramyocardial inflammation and cardiac fibrosis.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Asbun J, Villarreal FJ (2006) The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 47:693–700

    Article  PubMed  CAS  Google Scholar 

  2. Behrends M, Schulz R, Post H, Alexandrov A, Belosjorow S, Michel MC, Heusch G (2000) Inconsistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs. Am J Physiol Heart Circ Physiol 279:H1111–H1119

    PubMed  CAS  Google Scholar 

  3. Blam ME, Stein RB, Lichtenstein GR (2001) Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: current and future perspectives. Am J Gastroenterol 96:1977–1997

    PubMed  CAS  Google Scholar 

  4. Bristow MR (1998) Tumor necrosis factor-alpha and cardiomyopathy. Circulation 97:1340–1341

    PubMed  CAS  Google Scholar 

  5. Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, Thompson M, Giroir B (1998) Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 97:1375–1381

    PubMed  CAS  Google Scholar 

  6. Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A, Harken AH (1999) Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function. Crit Care Med 27:1309–1318

    Article  PubMed  CAS  Google Scholar 

  7. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor- alpha, in patients with moderateto- severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107:3133–3140

    Article  PubMed  CAS  Google Scholar 

  8. Clerk A, Harrison JG, Long CS, Sugden PH (1999) Pro-inflammatory cytokines stimulate mitogen-activated protein kinase subfamilies, increase phosphorylation of c-Jun and ATF2 and upregulate c-Jun protein in neonatal rat ventricular myocytes. J Mol Cell Cardiol 31:2087–2099

    Article  PubMed  CAS  Google Scholar 

  9. Dorge H, Schulz R, Belosjorow S, Post H, van de Sand A, Konietzka I, Frede S, Hartung T, Vinten-Johansen J, Youker KA, Entman ML, Erbel R, Heusch G (2002) Coronary microembolization: the role of TNF-alpha in contractile dysfunction. J Mol Cell Cardiol 34:51–62

    Article  PubMed  CAS  Google Scholar 

  10. Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, Patriotis C, Jenkins NA, Copeland NG, Kollias G, Tsichlis PN (2000) TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103:1071–1083

    Article  PubMed  CAS  Google Scholar 

  11. Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis. Basic Res Cardiol 102:279–297

    Article  PubMed  Google Scholar 

  12. Gullestad L, Aukrust P (2005) Review of trials in chronic heart failure showing broad-spectrum anti-inflammatory approaches. Am J Cardiol 95:17C–23C; discussion 38C–40C

    Article  PubMed  CAS  Google Scholar 

  13. Gurevitch J, Frolkis I, Yuhas Y, Lifschitz- Mercer B, Berger E, Paz Y, Matsa M, Kramer A, Mohr R (1997) Anti-tumor necrosis factor-alpha improves myocardial recovery after ischemia and reperfusion. J Am Coll Cardiol 30:1554–1561

    Article  PubMed  CAS  Google Scholar 

  14. Kadokami T, Frye C, Lemster B, Wagner CL, Feldman AM, McTiernan CF (2001) Anti-tumor necrosis factor-alpha antibody limits heart failure in a transgenic model. Circulation 104:1094–1097

    Article  PubMed  CAS  Google Scholar 

  15. Kannel WB, Hjortland M, Castelli WP (1974) Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 34:29–34

    Article  PubMed  CAS  Google Scholar 

  16. Karkar AM, Tam FW, Steinkasserer A, Kurrle R, Langner K, Scallon BJ, Meager A, Rees AJ (1995) Modulation of antibody- mediated glomerular injury in vivo by IL-1ra, soluble IL-1 receptor, and soluble TNF receptor. Kidney Int 48:1738–1746

    Article  PubMed  CAS  Google Scholar 

  17. Kelly RA, Smith TW (1997) Cytokines and cardiac contractile function.Circulation 95:778–781

    PubMed  CAS  Google Scholar 

  18. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM (1997) Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 81:627–635

    PubMed  CAS  Google Scholar 

  19. Labruto F, Yang J, Vaage J, Valen G (2005) Role of tumor necrosis factor alpha and its receptor I in preconditioning by hyperoxia. Basic Res Cardiol 100:198–207

    Article  PubMed  CAS  Google Scholar 

  20. Li M, Georgakopoulos D, Lu G, Hester L, Kass DA, Hasday J, Wang Y (2005) p38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart. Circulation 111:2494–2502

    Article  PubMed  CAS  Google Scholar 

  21. Libby P, Ross R (1996) Cytokines and growth regulatory molecules. In: Fuster V, Ross R, Topol EJ (eds) Lippincott- Raven, Philadelphia, p 585–594

  22. Liu X, Sun SQ, Hassid A, Ostrom RS (2006) cAMP Inhibits Transforming Growth Factor-beta-Stimulated Collagen Synthesis via Inhibition of Extracellular Signal-Regulated Kinase 1/2 and Smad Signaling in Cardiac Fibroblasts. Mol Pharmacol 70:1992–2003

    Article  PubMed  CAS  Google Scholar 

  23. Lorenz HM, Kalden JR (2002) Perspectives for TNF-alpha-targeting therapies. Arthritis Res 4(Suppl 3):S17–24

    Article  PubMed  Google Scholar 

  24. Mann DL (2003) Stress-activated cytokines and the heart: from adaptation to maladaptation. Annu Rev Physiol 65:81–101

    Article  PubMed  CAS  Google Scholar 

  25. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T (2004) Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109:1594–1602

    Article  PubMed  CAS  Google Scholar 

  26. Matsumori A, Yamada T, Suzuki H, Matoba Y, Sasayama S (1994) Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 72:561–566

    Article  PubMed  CAS  Google Scholar 

  27. Maury CP, Teppo AM (1989) Circulating tumour necrosis factor-alpha (cachectin) in myocardial infarction. J Intern Med 225:333–336

    Article  PubMed  CAS  Google Scholar 

  28. Miki T, Miura T, Tanno M, Nishihara M, Naitoh K, Sato T, Takahashi A, Shimamoto K (2007) Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway. Basic Res Cardiol 102:163–170

    Article  PubMed  CAS  Google Scholar 

  29. Millan J, Hewlett L, Glyn M, Toomre D, Clark P, Ridley AJ (2006) Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat Cell Biol 8(2):113–123

    Article  PubMed  CAS  Google Scholar 

  30. Noutsias M, Pauschinger M, Ostermann K, Escher F, Blohm JH, Schultheiss H, Kuhl U (2002) Digital image analysis system for the quantification of infiltrates and cell adhesion molecules in inflammatory cardiomyopathy. Med Sci Monit 8:MT59–MT71

    PubMed  CAS  Google Scholar 

  31. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP (1999) Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99:2750–2756

    PubMed  CAS  Google Scholar 

  32. Poornima IG, Parikh P, Shannon RP (2006) Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 98:596–605

    Article  PubMed  CAS  Google Scholar 

  33. Ruusalepp A, Czibik G, Flatebo T, Vaage J, Valen G (2007) Myocardial protection evoked by hyperoxic exposure involves signaling through nitric oxide and mitogen activated protein kinases. Basic Res Cardiol 102:318–326

    Article  PubMed  CAS  Google Scholar 

  34. Schulz R, Aker S, Belosjorow S, Heusch G (2004) TNFalpha in ischemia/reperfusion injury and heart failure. Basic Res Cardiol 99:8–11

    Article  PubMed  CAS  Google Scholar 

  35. Skyschally A, Gres P, Hoffmann S, Haude M, Erbel R, Schulz R, Heusch G (2007) Bidirectional role of tumor necrosis factor-alpha in coronary microembolization: progressive contractile dysfunction versus delayed protection against infarction. Circ Res 100:140–146

    Article  PubMed  CAS  Google Scholar 

  36. Takami S, Yamashita S, Kihara S, Kameda-Takemura K, Matsuzawa Y (1998) High concentration of glucose induces the expression of intercellular adhesion molecule-1 in human umbilical vein endothelial cells. Atherosclerosis 138:35–41

    Article  PubMed  CAS  Google Scholar 

  37. Thielmann M, Dorge H, Martin C, Belosjorow S, Schwanke U, van De Sand A, Konietzka I, Buchert A, Kruger A, Schulz R, Heusch G (2002) Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine. Circ Res 90:807–913

    Article  PubMed  CAS  Google Scholar 

  38. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL (1996) Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 93:704–711

    PubMed  CAS  Google Scholar 

  39. Tschope C, Walther T, Koniger J, Spillmann F, Westermann D, Escher F, Pauschinger M, Pesquero JB, Bader M, Schultheiss HP, Noutsias M (2004) Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. Faseb J 18:828–835

    Article  PubMed  CAS  Google Scholar 

  40. Tschope C, Walther T, Escher F, Spillmann F, Du J, Altmann C, Schimke I, Bader M, Sanchez-Ferrer CF, Schultheiss HP, Noutsias M (2005) Transgenic activation of the kallikreinkinin system inhibits intramyocardial inflammation, endothelial dysfunction, and oxidative stress in experimental diabetic cardiomyopathy. Faseb J 19:2057–2059

    PubMed  Google Scholar 

  41. Tschope C, Walther T, Escher F, Spillmann F, Du J, Altmann C, Schimke I, Bader M, Sanchez-Ferrer CF, Schultheiss HP, Noutsias M (2005) Transgenic activation of the kallikreinkinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. Faseb J 19:2057–2059

    PubMed  Google Scholar 

  42. Valen G (2004) Signal transduction through nuclear factor kappa B in ischemia-reperfusion and heart failure. Basic Res Cardiol 99:1–7

    Article  PubMed  CAS  Google Scholar 

  43. Westermann D, Rutschow S, Van Linthout S, Linderer A, Bucker-Gartner C, Sobirey M, Riad A, Pauschinger M, Schultheiss HP, Tschope C (2006) Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia 49:2507–2513

    Article  PubMed  CAS  Google Scholar 

  44. Westermann D, Rutschow S, Jager S, Linderer A, Anker S, Riad A, Unger T, Schultheiss HP, Pauschinger M, Tschope C (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56:641–646

    Article  PubMed  CAS  Google Scholar 

  45. Westermann D, Van Linthout S, Dhayat S, Dhayat N, Escher F, Bucker-Gartner C, Spillmann F, Noutsias M, Riad A, Schultheiss H-P, Tschope C (2007) Cardioprotective and anti inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy. In, p db06–1662

  46. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL (1993) Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 92:2303–2312

    Article  PubMed  CAS  Google Scholar 

  47. Zhang M, Tracey KJ (1998) Tumor necrosis factor. In: AW T (ed) The Cytokine handbook. Academic Press, San Diego, Californie, p 517–548

Download references

Author information

Authors and Affiliations

  1. Dept. of Cardiology and Pneumonology, Charité — Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    D. Westermann, S. Van Linthout, S. Dhayat, N. Dhayat, M. Noutsias, F. Spillmann, A. Riad, H.-P. Schultheiss & C. Tschöpe MD

  2. Dept. of Pharmacology and Toxicology, Charité — Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    A. Schmidt

  3. Centocor, Malvern (PA), USA

    X.-Y. Song

Authors
  1. D. Westermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Van Linthout
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Dhayat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Dhayat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Noutsias
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X.-Y. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Spillmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Riad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H.-P. Schultheiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C. Tschöpe MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Tschöpe MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Westermann, D., Van Linthout, S., Dhayat, S. et al. Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 102, 500–507 (2007). https://doi.org/10.1007/s00395-007-0673-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-007-0673-0

Key words

Search

Navigation