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  • 1 Universidade Estadual de Campinas (UNICAMP) Departamento de Anatomia, Instituto de Biologia Celular, Fisiologia e Biofisica CP 6109 13083-970 Campinas, SP Brazil
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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/mm 2 in control vs 102 ± 9 cells/mm 2 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.

  • Benjamin, J. (2001) Matrix metalloproteinases: from biology to therapeutic strategies in cardiovascular disease. J. Investig. Med. 49 , 381–397.

    Benjamin J. , 'Matrix metalloproteinases: from biology to therapeutic strategies in cardiovascular disease ' (2001 ) 49 J. Investig. Med. : 381 -397.

    • Search Google Scholar
  • Boger, R. H. (2008) L-Arginine therapy in cardiovascular pathologies: beneficial or dangerous? Curr. Opin. Clin. Nutr. Metab. Care 11 , 55–61.

    Boger R. H. , 'L-Arginine therapy in cardiovascular pathologies: beneficial or dangerous? ' (2008 ) 11 Curr. Opin. Clin. Nutr. Metab. Care : 55 -61.

    • Search Google Scholar
  • 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.

    Bing O. H. L. , 'L-Arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat ' (2009 ) 22 Am. J. Hypert. : 228 -234.

    • Search Google Scholar
  • 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.

    Faulkner A. J. , 'Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma ' (2007 ) 21 FASEB J. : 2195 -2204.

    • Search Google Scholar
  • 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.

    Mornet D. , 'Alpha 7B integrin changes in mdx mouse muscles after L-arginine administration ' (2005 ) 579 FEBS Lett. : 1079 -1184.

    • Search Google Scholar
  • 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 metalloproteinase-4. FEBS Lett. 582 , 1135–1140.

    Zichel M. , 'Peroxynitrite inactivates human-tissue inhibitor of metalloproteinase-4 ' (2008 ) 582 FEBS Lett. : 1135 -1140.

    • Search Google Scholar
  • Eberhardt, W., Pfeilschifter, J. (2007) Nitric oxide and vascular remodeling: Spotlight on the kidney. Kidney Int. 72 , S9–S16.

    Pfeilschifter J. , 'Nitric oxide and vascular remodeling: Spotlight on the kidney ' (2007 ) 72 Kidney Int. : S9 -S16.

    • Search Google Scholar
  • Finsterer, J., Stollberger, C. (2008) Primary myopathies and the heart. Scand. Cardiovasc. J. 42 , 9–24.

    Stollberger C. , 'Primary myopathies and the heart ' (2008 ) 42 Scand. Cardiovasc. J. : 9 -24.

    • Search Google Scholar
  • Frankel, K. A., Rosser, R. J. (1976) The pathology of the heart in progressive muscular dystrophy: Epimyocardial fibrosis. Hum. Pathol. 7 , 375–386.

    Rosser R. J. , 'The pathology of the heart in progressive muscular dystrophy: Epimyocardial fibrosis ' (1976 ) 7 Hum. Pathol. : 375 -386.

    • Search Google Scholar
  • 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.

    Mizuguchi T. H. , 'Imidaprilat inhibits matrix metalloproteinase-2 activity in human cardiac fibroblasts induced by interleukin-1 beta via NO-dependent pathway ' (2008 ) 126 Int. J. Cardiol. : 414 -420.

    • Search Google Scholar
  • Hoffman, E. P., Brown, R. J., Kunkel, L. M. (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51 , 919–928.

    Kunkel L. M. , 'Dystrophin: the protein product of the Duchenne muscular dystrophy locus ' (1987 ) 51 Cell : 919 -928.

    • Search Google Scholar
  • Hnia, K., Gayraud, J., Hugon, G., Ramonatxo, M., Porte, S. D. L., Matecki, S., Mornet, D. (2008) L-arginine decreases inflammation and modulates the nuclear factor-kappa B/matrix metalloproteinase cascade in mdx muscle fibers. Am. J. Pathol. 172 , 1509–1519.

    Mornet D. , 'L-arginine decreases inflammation and modulates the nuclear factor-kappa B/matrix metalloproteinase cascade in mdx muscle fibers ' (2008 ) 172 Am. J. Pathol. : 1509 -1519.

    • Search Google Scholar
  • Markham, L. W., Spicer, R. L., Khoury, P. R., Wong, B. L., Mathews, K. D., Cripe, L. H. (2005) Steroid therapy and cardiac function in Duchenne muscular dystrophy. Pediatr. Cardiol. 26 , 768–771.

    Cripe L. H. , 'Steroid therapy and cardiac function in Duchenne muscular dystrophy ' (2005 ) 26 Pediatr. Cardiol. : 768 -771.

    • Search Google Scholar
  • 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.

    Santo Neto H. , 'Long-term therapy with deflazacort decreases myocardial fibrosis in mdx mice ' (2009 ) 40 Muscle Nerve : 466 -468.

    • Search Google Scholar
  • 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.

    Matthews D. E. , 'Nitric oxide regulation of MMP-9 activation and its relationship to modifications of the cysteine switch ' (2008 ) 47 Biochemistry : 5832 -5840.

    • Search Google Scholar
  • Migita, K., Maeda, Y., Abiru, S. (2005) Peroxynitrite-mediated matrix metalloproteinase-2 activation in human hepatic stellate cell. FEBS Lett. 579 , 3119–3125.

    Abiru S. , 'Peroxynitrite-mediated matrix metalloproteinase-2 activation in human hepatic stellate cell ' (2005 ) 579 FEBS Lett. : 3119 -3125.

    • Search Google Scholar
  • Morbidelli, L., Donini, S., Ziche, M. (2003) Role of nitric oxide in the modulation of angiogenesis. Curr. Pharm. Des. 9 , 521–530.

    Ziche M. , 'Role of nitric oxide in the modulation of angiogenesis ' (2003 ) 9 Curr. Pharm. Des. : 521 -530.

    • Search Google Scholar
  • 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.

    Bain R. J. I. , 'The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy ' (1990 ) 26 Int. J. Cardiol. : 271 -277.

    • Search Google Scholar
  • Pacher, P., Beckman, J. S., Liaudet, L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87 , 315–324.

    Liaudet L. , 'Nitric oxide and peroxynitrite in health and disease ' (2007 ) 87 Physiol. Rev. : 315 -324.

    • Search Google Scholar
  • 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.

    Levin L. , 'Evolution of the mdx mouse cardiomyopathy: physiological and morphological findings ' (2004 ) 14 Neuromuscul. Disord. : 491 -496.

    • Search Google Scholar
  • 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.

    Marques M. J. , 'L-arginine enhances muscle regeneration after experimental envenomation by B. jararacussu: A future for nitric oxide-based therapy? ' (2006 ) 48 Toxicon : 353 -357.

    • Search Google Scholar
  • 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.

    Bernatova I. , 'L-arginine fails to protect against myocardial remodeling in L-NAME-induced hypertension ' (2005 ) 35 Eur. J. Clin. Invest. : 362 -368.

    • Search Google Scholar
  • Spinale, F. G. (2002) Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ. Res. 90 , 520–530.

    Spinale F. G. , 'Matrix metalloproteinases: regulation and dysregulation in the failing heart ' (2002 ) 90 Circ. Res. : 520 -530.

    • Search Google Scholar
  • Spinale, F. G. (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 87 , 1285–1342.

    Spinale F. G. , 'Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function ' (2007 ) 87 Physiol. Rev. : 1285 -1342.

    • Search Google Scholar
  • 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.

    Hoffman E. P. , 'Dystrophin-deficient cardiomyopathy in mouse: expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart ' (2008 ) 18 Neuromuscul. Disor. : 371 -381.

    • Search Google Scholar
  • 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.

    Wink D. A. , 'The chemical biology of nitric oxide: Implications in cellular signaling ' (2008 ) 45 Free Radic. Biol. Med. : 18 -31.

    • Search Google Scholar
  • van Erp, C., Hoey, A. (2004) Effect of L-arginine on cardiac function in mdx mice. J. Mol. Cel. Cardiol. 37 , 170–171.

    Hoey A. , 'Effect of L-arginine on cardiac function in mdx mice ' (2004 ) 37 J. Mol. Cel. Cardiol. : 170 -171.

    • Search Google Scholar
  • 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.

    Tidball J. G. , 'Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium ' (2005 ) 14 Hum. Mol. Genet. : 1921 -1933.

    • Search Google Scholar
  • 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.

    Allen D. G. , 'The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice ' (2007 ) 293 Am. J. Physiol. Heart Circ. Physiol. : 1969 -1977.

    • Search Google Scholar
  • 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.

    Cooke J. P. , 'L-arginine supplementation in peripheral arterial disease - No benefit and possible harm ' (2007 ) 116 Circulation : 188 -195.

    • Search Google Scholar
  • 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.

    Mora M. , 'Altered extracellular matrix transcript expression and protein modulation in primary Duchenne muscular dystrophy myotubes ' (2007 ) 26 Matrix Biol. : 615 -624.

    • Search Google Scholar