Skip to main content
SpringerLink
Log in

FR167653 suppresses the progression of experimental autoimmune myocarditis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Experimental autoimmune myocarditis (EAM) induced in rats by injection of cardiac myosin is an animal model of human myocarditis and post-myocarditis dilated cardiomyopathy. It has been reported that proinflammatory cytokines play crucial roles in the induction of EAM and in the progression of myocardial injury in this disease. FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl) pyrazolo [5,1-c] [1,2,4] triazin-2-yl]-2-phenylethanedione sulfate monohydrate) as been reported to suppress tumor necrosis factor-alpha (TNF-α). We hypothesized that FR167653 would suppress the progression of EAM if TNF-α and/or interleukin-1 beta (IL-1β) were the culprit cytokines in EAM. To investigate the effects of FR167653 in EAM, FR167653 was given to rats for 4 weeks, immediately after they had been immunized with cardiac myosin. The ratio of heart weight to body weight and the area of inflammatory lesions were less in the FR167653 groups than in the control rats. FR167653 reduced serum sialic acid levels significantly. The control group showed a deterioration in cardiac function. The FR167653 groups had significantly better hemodynamic parameters, including improved left ventricular end-diastolic pressure, central venous pressure, aortic pressure, and positive and negative left ventricular pressure derivatives. mRNA expression of IL-1β in the heart was significantly lower in rats given FR167653. However, mRNA of TNF-α was not detected in any groups. Our results suggest that FR167653 suppresses the development of myocarditis by suppression of IL-1β.

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. Davidoff R, Palacios I, Southern J, Fallon JT, Newell J, Dec GW: Giant cell vs. lymphocytic myocarditis. A comparison of their clinical features and long-term outcomes. Circulation 83: 953-961, 1991

    Google Scholar 

  2. Cooper LT Jr, Berry GJ, Shabetai R: Idiopathic giant-cell myocarditis — natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 336: 1860-1866, 1997

    Google Scholar 

  3. Neu N, Rose NR, Beisel KW, Herskowitz A, Gurri-Glass G, Craig SW: Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol 139: 3630-3636, 1987

    Google Scholar 

  4. Kodama M, Matsumoto Y, Fujiwara M, Masani F, Izumi T, Shibata A: A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction. Clin Immunol Immunopathol 57: 250-262, 1990

    Google Scholar 

  5. Kodama M, Hanawa H, Saeki M, Hosono H, Inomata T, Suzuki K, Shibata A: Rat dilated cardiomyopathy after autoimmune giant cell myocarditis. Circ Res 75: 278-284, 1994

    Google Scholar 

  6. Smith SC, Allen PM: Myosin-induced acute myocarditis is a T cell-mediated disease. J Immunol 147: 2141-2147, 1991

    Google Scholar 

  7. Kodama M, Matsumoto Y, Fujiwara M: In vivo lymphocyte-mediated myocardial injuries demonstrated by adoptive transfer of experimental autoimmune myocarditis. Circulation 85: 1918-1926, 1992

    Google Scholar 

  8. Okura Y, Takeda K, Honda S, Hanawa H, Watanabe H, Kodama M, Izumi T, Aizawa Y, Seki S, Abo T: Recombinant murine interleukin-12 facilitates induction of cardiac myosin-specific type 1 helper T cells in rats. Circ Res 82: 1035-1042, 1998

    Google Scholar 

  9. Okura Y, Yamamoto T, Goto S, Inomata T, Hirono S, Hanawa H, Feng L, Wilson CB, Kihara I, Izumi T, Shibata A, Aizawa Y, Seki S, Abo T: Characterization of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats. J Mol Cell Cardiol 29: 491-502, 1997

    Google Scholar 

  10. Smith SC, Allen PM: Neutralization of endogenous tumor necrosis factor ameliorates the severity of myosin-induced myocarditis. Circ Res 70: 856-863, 1992

    Google Scholar 

  11. Yamamoto N, Sakai F, Yamazaki H, Nakahara K, Okuhara M: Effect of FR167653, a cytokine suppressive agent, on endotoxin-induced disseminated intravascular coagulation. Eur J Pharmacol 314: 137-142, 1996

    Google Scholar 

  12. Aiba M, Takeyoshi I, Ohwada S, Kobayashi J, Iwanami K, Sunose Y, Kawashima Y, Mastumoto K, Muramoto M, Morishita Y: Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs. J Am Coll Surg 191: 251-258., 2000

    Google Scholar 

  13. Otani Y, Takeyoshi I, Koibuchi Y, Matsumoto K, Muramoto M, Morishita Y: The effect of FR167653 on pulmonary ischemia-reperfusion injury in rats. J Heart Lung Transplant 19: 377-383, 2000

    Google Scholar 

  14. Ohashi N, Matsumori A, Furukawa Y, Ono K, Okada M, Iwasaki A, Miyamoto T, Nakano A, Sasayama S: Role of p38 mitogen-activated protein kinase in neointimal hyperplasia after vascular injury. Arterioscler Thromb Vasc Biol 20: 2521-2526, 2000

    Google Scholar 

  15. Inomata T, Hanawa H, Miyanishi T, Yajima E, Nakayama S, Maita T, Kodama M, Izumi T, Shibata A, Abo T: Localization of porcine cardiac myosin epitopes that induce experimental autoimmune myocarditis. Circ Res 76: 726-733, 1995

    Google Scholar 

  16. Hirono S, Islam MO, Nakazawa M, Yoshida Y, Kodama M, Shibata A, Izumi T, Imai S: Expression of inducible nitric oxide synthase in rat experimental autoimmune myocarditis with special reference to changes in cardiac hemodynamics. Circ Res 80: 11-20, 1997

    Google Scholar 

  17. Feng L, Tang WW, Loskutoff DJ, Wilson CB: Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis. J Am Soc Nephrol 3: 1753-1764, 1993

    Google Scholar 

  18. Sambrook JF: Molecular Cloning. In: A Laboratory Manual. Cold Spring Harbor Lab., New York, 1989, pp 71-78

    Google Scholar 

  19. Yamamoto T, Sasaki S, Fushimi K, Ishibashi K, Yaoita E, Kawasaki K, Fujinaka H, Marumo F, Kihara I: Expression of AQP family in rat kidneys during development and maturation. Am J Physiol 272: F198-F204, 1997

    Google Scholar 

  20. Ponassi M, Jacques TS, Ciani L, Constant CF: Expression of the rat homologue of the Drosophila fat tumour suppressor gene. Mech Dev 80: 207-212, 1999

    Google Scholar 

  21. Masters DB, Griggs CT, Berde CB: High sensitivity quantification of RNA from gels and autoradiograms with affordable optical scanning. Biotechniques 12: 902-906, 908–911, 1992

    Google Scholar 

  22. Doumas BT, Watson WA, Biggs HG: Albumin standards and the measurement of serum albumin with bromcresol green. Clin Chim Acta 31: 87-96, 1971

    Google Scholar 

  23. Sugahara K, Sugimoto K, Nomura O, Usui T: Enzymatic assay of serum sialic acid. Clin Chim Acta 108: 493-498, 1980

    Google Scholar 

  24. Sillanaukee P, Ponnio M, Jaaskelainen IP: Occurrence of sialic acids in healthy humans and different disorders. Eur J Clin Invest 29: 413-425, 1999

    Google Scholar 

  25. Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE: A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 333: 269-275, 1995

    Google Scholar 

  26. Kodama M, Oda H, Okabe M, Aizawa Y: Early and long-term mortality of the clinical subtypes of myocarditis. Jpn Circ J 65: 961-964, 2001

    Google Scholar 

  27. McCarthy RE 3rd, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Hare JM, Baughman KL: Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 342: 690-695, 2000

    Google Scholar 

  28. Mendes LA, Picard MH, Dec GW, Hartz VL, Palacios IF, Davidoff R: Ventricular remodeling in active myocarditis. Myocarditis Treatment Trial. Am Heart J 138: 303-308, 1999

    Google Scholar 

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

    Google Scholar 

  30. Siwik DA, Chang DL, Colucci WS: Interleukin-1 beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res 86: 1259-1265, 2000

    Google Scholar 

  31. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R: Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87: 241-247, 2000

    Google Scholar 

  32. Zhang S, Kodama M, Hanawa H, Izumi T, Shibata A, Masani F: Effects of cyclosporine, prednisolone and aspirin on rat autoimmune giant cell myocarditis. J Am Coll Cardiol 21: 1254-1260, 1993

    Google Scholar 

  33. Hanawa H, Kodama M, Zhang S, Izumi T, Shibata A: An immunosup-pressant compound, FK-506, prevents the progression of autoimmune myocarditis in rats. Clin Immunol Immunopathol 62: 321-326, 1992

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. First Department of Internal Medicine, Institute of Nephrology, Niigata University School of Medicine, Niigata, Japan

    Seitaro Maruyama, Kiminori Kato, Makoto Kodama, Yuji Okura, Satoru Hirono, Koichi Fuse, Haruo Hanawa, Osamu Nakagawa & Yoshifusa Aizawa

  2. Department of Medical Technology, Institute of Nephrology, Niigata University School of Medicine, Niigata, Japan

    Mikio Nakazawa

  3. Department of Laboratory Medicine, Institute of Nephrology, Niigata University School of Medicine, Niigata, Japan

    Takashi Miida

  4. Department of Pathology, Institute of Nephrology, Niigata University School of Medicine, Niigata, Japan

    Eisin Yaoita & Tadashi Yamamoto

  5. The Fourth Department of Internal Medicine, Saitama Medical Schook, Saitama, Japan

    Ikuo Inoue

Authors
  1. Seitaro Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiminori Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Makoto Kodama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuji Okura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoru Hirono
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Koichi Fuse
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haruo Hanawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Osamu Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mikio Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takashi Miida
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eisin Yaoita
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tadashi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ikuo Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yoshifusa Aizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maruyama, S., Kato, K., Kodama, M. et al. FR167653 suppresses the progression of experimental autoimmune myocarditis. Mol Cell Biochem 246, 39–44 (2003). https://doi.org/10.1023/A:1023447710638

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1023447710638

Search

Navigation