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Acta Biologica Hungarica

, Volume 61, Issue 2, pp 168–174 | Cite as

Myocardial Fibrosis is Unaltered by Long-Term Administration of L-Arginine in Dystrophin Deficient Mdx Mice: A Histomorphometric Analysis

  • Maria Julia MarquesEmail author
  • Isabel Cristina Chagas Barbin
  • Ana Paula Tiemi Taniguti
  • Daniela Silva Oggian
  • R. Ferretti
  • H. Santo Neto
Article

Abstract

Cardiac failure secondary to myocardial fibrosis (MF) significantly contributes to death in Duchenne muscular dystrophy (DMD), a fatal form of muscle disease. In aging, the mdx mice, an animal model of DMD, MF is similar to that observed in humans. Nitric oxide-based therapy has been proposed to retard MF in DMD and a candidate is L-arginine (L-arg). In this study we evaluated the effects of long-term therapy with L-arg in the MF of mdx mice. Mdx mice (6 months old) were treated with L-arg in drinking water. Control mdx mice received water only. After 15 months of treatment, hearts were stained with Masson’s trichrome for analysis of MF and with hematoxilyn and eosin for analysis of inflammation and cardiomyocyte damage. We observed that MF was not affected (29.5 ±2.5% of MF area for control vs 31.4±2% for L-arginine-treated animals; P>0.05). The density of inflammatory cells was reduced (169±12 cells/mm2 in control vs 102±9 cells/mm2 in L-arg-treated; P<0.05). The present study shows that long-term administration of L-arg is not effective in retarding MF in mdx dystrophinopathy

Keywords

Cardiac failure cardiac fibrosis cardiomyopathy Duchenne muscular dystrophy 

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Notes

Acknowledgements

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grants 95/6110-2, 01/00570-4 and 04/15526-9). H. S. N. and M. J. M. are recipients of fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grants 301386/07-2, 302006/09-5 and 474708/06-3). A.P.T.T. is the recipient of a CNPq fellowship.

References

  1. 1.
    Benjamin, J. (2001) Matrix metalloproteinases: from biology to therapeutic strategies in cardiovascular disease. J. Investig. Med. 49, 381–397.CrossRefGoogle Scholar
  2. 2.
    Boger, R. H. (2008) L-Arginine therapy in cardiovascular pathologies: beneficial or dangerous? Curr. Opin. Clin. Nutr. Metab. Care 11, 55–61.CrossRefGoogle Scholar
  3. 3.
    Brooks, W. W., Conrad, C. H., Robinson, K. G., Colucci, W. S., Bing, O. H. L. (2009) L-Arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat. Am. J. Hypert. 22, 228–234.CrossRefGoogle Scholar
  4. 4.
    Chamberlain, S. J., Metzger, J., Reyes, M., Townsend, D., Faulkner, A. J. (2007) Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma. FASEB J. 21, 2195–2204.CrossRefGoogle Scholar
  5. 5.
    Chazalette, D., Hnia, K., Rivier, F., Hugon, G., Mornet, D. (2005) Alpha 7B integrin changes in mdx mouse muscles after L-arginine administration. FEBS Lett. 579, 1079–1184.CrossRefGoogle Scholar
  6. 6.
    Donnini, S., Monti, M., Roncone, R., Morbidelli, L., Rocchigiani, M., Oliviero, S., Casella, L., Giachetti, A., Schulz, R., Zichel, M. (2008) Peroxynitrite inactivates human-tissue inhibitor of metal-loproteinase-4. FEBS Lett. 582, 1135–1140.CrossRefGoogle Scholar
  7. 7.
    Eberhardt, W., Pfeilschifter, J. (2007) Nitric oxide and vascular remodeling: Spotlight on the kidney. Kidney Int. 72, S9–S16.CrossRefGoogle Scholar
  8. 8.
    Finsterer, J., Stollberger, C. (2008) Primary myopathies and the heart. Scand. Cardiovasc. J. 42, 9–24.CrossRefGoogle Scholar
  9. 9.
    Frankel, K. A., Rosser, R. J. (1976) The pathology of the heart in progressive muscular dystrophy: Epimyocardial fibrosis. Hum. Pathol. 7, 375–386.CrossRefGoogle Scholar
  10. 10.
    Guo, X. G., Uzui, H. Y., Mizuguchi, T. H. (2008) Imidaprilat inhibits matrix metalloproteinase-2 activity in human cardiac fibroblasts induced by interleukin-1 beta via NO-dependent pathway. Int. J. Cardiol. 126, 414–420.CrossRefGoogle Scholar
  11. 11.
    Hoffman, E. P., Brown, R. J., Kunkel, L. M. (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919–928.CrossRefGoogle Scholar
  12. 12.
    Hnia, K., Gayraud, J., Hugon, G., Ramonatxo, M., Porte, S. D. L., Matecki, S., Momet, D. (2008) L-arginine decreases inflammation and modulates the nuclear factor-kappa B/matrix metalloprotei-nase cascade in mdx muscle fibers. Am. J. Pathol. 172, 1509–1519.CrossRefGoogle Scholar
  13. 13.
    Markham, L. W., Spicer, R. L., Khoury, P. P., Wong, B. L., Mathews, K. D., Cripe, L. H. (2005) Steroid therapy and cardiac function in Duchenne muscular dystrophy. Pediatr. Cardiol. 26, 768–771.CrossRefGoogle Scholar
  14. 14.
    Marques, M. J., Oggiam, D. S., Barbin, I. C. C., Ferretti, R., Santo Neto, H. (2009) Long-term therapy with deflazacort decreases myocardial fibrosis in mdx mice. Muscle Nerve 40, 466–468.CrossRefGoogle Scholar
  15. 15.
    McCarthy, S. M., Bove, P. F., Matthews, D. E. (2008) Nitric oxide regulation of MMP-9 activation and its relationship to modifications of the cysteine switch. Biochemistry 47, 5832–5840.CrossRefGoogle Scholar
  16. 16.
    Migita, K., Maeda, Y., Abiru, S. (2005) Peroxynitrite-mediated matrix metalloproteinase-2 activation in human hepatic stellate cell. FEBS Lett. 579, 3119–3125.CrossRefGoogle Scholar
  17. 17.
    Morbidelli, L., Donini, S., Ziche, M. (2003) Role of nitric oxide in the modulation of angiogenesis. Curr. Pharm. Des. 9, 521–530.CrossRefGoogle Scholar
  18. 18.
    Nigro, G., Comi, L. I., Politano, L., Bain, R. J. I. (1990) The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int. J. Cardiol. 26, 271–277.CrossRefGoogle Scholar
  19. 19.
    Pacher, P., Beckman, J. S., Liaudet, L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315–324.CrossRefGoogle Scholar
  20. 20.
    Quinlan, J., Hahn, H., Wong, B., Lorenz, J., Wenisch, A., Levin, L. (2004) Evolution of the mdx mouse cardiomyopathy: physiological and morphological findings. Neuromuscul. Disord 14, 491–496.CrossRefGoogle Scholar
  21. 21.
    Santo Neto, H., Vomero, V. U., Marques, M. J. (2006) L-arginine enhances muscle regeneration after experimental envenomation by B. jararacussu: A future for nitric oxide-based therapy? Toxicon 48, 353–357.CrossRefGoogle Scholar
  22. 22.
    Simko, F., Luptak, I., Matuskova, J., Krajcirovicova, K., Sumbalova, Z., Kucharska, J., Gvozdjakova, A., Simko, J., Babal, P., Pechanova, O., Bernatova, I. (2005) L-arginine fails to protect against myocardial remodeling in L-NAME-induced hypertension. Eur. J. Clin. Invest. 35, 362–368.CrossRefGoogle Scholar
  23. 23.
    Spinale, F. G. (2002) Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ. Res. 90, 520–530.CrossRefGoogle Scholar
  24. 24.
    Spinale, F. G. (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 87, 1285–1342.CrossRefGoogle Scholar
  25. 25.
    Spurney, C. F., Knoblach, S., Pistilli, E. E., Nagaraju, K., Martin, G. R., Hoffman, E. P. (2008) Dystrophin-deficient cardiomyopathy in mouse: expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart. Neuromuscul. Disor. 18, 371–381.CrossRefGoogle Scholar
  26. 26.
    Thomas, D. D., Ridnour, L. A., Isenberg, J. S., Flores-Santana, W., Switzer, C. H., Donzelli, S., Hussain, P., Vecoli, C., Paolocci, N., Ambs, S., Colton, C. A., Harris, C. C., Roberts, D. D., Wink, D. A. (2008) The chemical biology of nitric oxide: Implications in cellular signaling. Free Radic. Biol Med 45, 18–31.CrossRefGoogle Scholar
  27. 27.
    van Erp, C., Hoey, A. (2004) Effect of L-arginine on cardiac function in mdx mice. J. Mol. Cel. Cardiol. 37, 170–171.Google Scholar
  28. 28.
    Wehling-Henricks, M., Jordan, M. C., Roos, K. P., Deng, B., Tidball, J. G. (2005) Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium. Hum. Mol. Genet. 14, 1921–1933.CrossRefGoogle Scholar
  29. 29.
    Williams, I. A., Allen, D. G. (2007) The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice. Am. J. Physiol. Heart Circ. Physiol. 293, 1969–1977.CrossRefGoogle Scholar
  30. 30.
    Wilson, A. M., Harada, R., Nair, N., Balasubramanian, N., Cooke, J. P. (2007) L-arginine supplementation in peripheral arterial disease - No benefit and possible harm. Circulation 116, 188–195.CrossRefGoogle Scholar
  31. 31.
    Zanotti, S., Saredi, S., Ruggieri, A., Fabbri, M., Blasevich, F., Romaggi, S., Morandi, L., Mora, M. (2007) Altered extracellular matrix transcript expression and protein modulation in primary Duchenne muscular dystrophy myotubes. Matrix Biol. 26, 615–624.CrossRefGoogle Scholar

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© Akadémiai Kiadó, Budapest 2010

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Maria Julia Marques
    • 1
    Email author
  • Isabel Cristina Chagas Barbin
    • 1
  • Ana Paula Tiemi Taniguti
    • 1
  • Daniela Silva Oggian
    • 1
  • R. Ferretti
    • 1
  • H. Santo Neto
    • 1
  1. 1.Departamento de Anatomia, Instituto de Biologia Celular, Fisiologia e BiofisicaUniversidade Estadual de Campinas (UNICAMP)CampinasBrazil

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