Recent studies showed that chronic administration of losartan, an angiotensin II type I receptor antagonist, improved skeletal muscle function in dystrophin-deficient mdx mice. In this study, C57BL/10ScSn-Dmdmdx/J female mice were either untreated or treated with losartan (n = 15) in the drinking water at a dose of 600 mg/L over a 6-month period. Cardiac function was assessed via in vivo high frequency echocardiography and skeletal muscle function was assessed using grip strength testing, Digiscan monitoring, Rotarod timing, and in vitro force testing. Fibrosis was assessed using picrosirius red staining and Image J analysis. Gene expression was evaluated using real-time polymerized chain reaction (RT-PCR). Percentage shortening fraction was significantly decreased in untreated (26.9% ± 3.5%) mice compared to losartan-treated (32.2% ± 4.2%; P < .01) mice. Systolic blood pressure was significantly reduced in losartan-treated mice (56 ± 6 vs 69 ± 7 mm Hg; P < .0005). Percentage cardiac fibrosis was significantly reduced in losartan-treated hearts (P < .05) along with diaphragm (P < .01), extensor digitorum longus (P < .05), and gastrocnemius (P < .05) muscles compared to untreated mdx mice. There were no significant differences in skeletal muscle function between treated and untreated groups. Chronic treatment with losartan decreases cardiac and skeletal muscle fibrosis and improves cardiac systolic function in dystrophin-deficient mdx mice.
Hoffman EP, Brown RH Jr, Kunkel LMDystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987; 51(6):919-928.
2.
Gulati S., Saxena A., Kumar V., Kalra V.Duchenne muscular dystrophy: prevalence and patterns of cardiac involvement . Indian J Pediatr. 2005;72(5):389-393.
3.
Ramaciotti C. , Heistein LC, Coursey M., et al. Left ventricular function and response to enalapril in patients with duchenne muscular dystrophy during the second decade of life. Am J Cardiol. 2006;98(6):825-827.
4.
Jefferies JL , Eidem BW, Belmont JW, et al. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation . 2005;112(18):2799-2804.
5.
Duboc D., Meune C., Lerebours G., Devaux JY, Vaksmann G., Becane HMEffect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol. 2005;45(6):855-857.
6.
Duboc D., Meune C., Pierre B., et al. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ follow-up. Am Heart J. 2007;154(3):596-602.
7.
Khan R., Sheppard R.Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology . 2006;118(1):10-24.
8.
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005; 112(12):e154-e235.
9.
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312(5770):117-121.
10.
Cohn RD, van Erp C., Habashi JP, et al. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med. 2007;13(2): 204-210.
11.
Matsuhisa S. , Otani H., Okazaki T., et al. N-acetylcysteine abolishes the protective effect of losartan against left ventricular remodeling in cardiomyopathy hamster . Antioxid Redox Signal. 2008;10(12):1999-2008.
12.
Raben N., Nagaraju K., Lee E., Plotz P.Modulation of disease severity in mice with targeted disruption of the acid alpha-glucosidase gene. Neuromuscul Disord. 2000;10(4-5):283-291.
13.
Spurney CF, Gordish-Dressman H., Guerron AD, et al. Preclinical drug trials in the mdx mouse: assessment of reliable and sensitive outcome measures. Muscle Nerve. 2009;39(5):591-602.
14.
Nagaraju K. , Raben N., Loeffler L., et al. Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Proc Natl Acad Sci. 2000;97(16):9209-14.
15.
Brooks SV, Faulkner JAContractile properties of skeletal muscles from young, adult and aged mice . J Physiol. 1988;404:71-82.
16.
Spurney CF, Knoblach S., Pistilli EE, Nagaraju K., Martin GR, Hoffman EPDystrophin-deficient cardiomyopathy in mouse: expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart. Neuromuscul Disord. 2008;18(5):371-381.
17.
Quinlan JG, Hahn HS, Wong BL, Lorenz JN, Wenisch AS, Levin LSEvolution of the mdx mouse cardiomyopathy: physiological and morphological findings. Neuromuscul Disord. 2004; 14(8-9):491-496.
18.
Bauer R., Straub V., Blain A., Bushby K., MacGowan GAContrasting effects of steroids and angiotensin-converting-enzyme inhibitors in a mouse model of dystrophin-deficient cardiomyopathy. Eur J Heart Fail.2009;11(5):463-471.
19.
Spurney CF, Cha HJ, Sali A., et al. Evaluation of skeletal and cardiac muscle function after chronic administration of thymosin beta-4 in the dystrophin deficient mouse. PLoS One. 2010;5(1): e8976.
20.
Li W., Liu W., Zhong J., Yu X.Early manifestation of alteration in cardiac function in dystrophin deficient mdx mouse using 3D CMR tagging. J Cardiovasc Magn Reson. 2009;11:40.
21.
Marques MJ, Oggiam DS, Barbin IC, Ferretti R., Santo Neto H.Long-term therapy with deflazacort decreases myocardial fibrosis in mdx mice . Muscle Nerve. 2009;40(3):466-468.
22.
Kanda T., Araki M., Nakano M., et al. Chronic effect of losartan in a murine model of dilated cardiomyopathy: comparison with captopril. J Pharmacol Exp Ther. 1995;273(2):955-958.
23.
Lim DS, Lutucuta S., Bachireddy P., et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation . 2001;103(6): 789-791.
24.
Fredj S., Bescond J., Louault C., Delwail A., Lecron JC, Potreau D.Role of interleukin-6 in cardiomyocyte/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation. J Cell Physiol . 2005;204(2):428-436.
25.
Goncalves G. , Zornoff LA, Ribeiro HB, et al. [Blockade of reninangiotensin system attenuates cardiac remodeling in rats undergoing aortic stenosis]. Arq Bras Cardiol. 2005;84(4):304-308.
26.
Oishi Y., Ozono R., Yoshizumi M., Akishita M., Horiuchi M., Oshima T.AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling. Life Sci. 2006;80(1):82-88.
27.
Ji Y., Liu J., Wang Z., Liu N. Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells. Cell Physiol Biochem.2009; 23(4-6):265-276.
28.
Tang TF, Zhou QL, Zhu LL, Tang R., Ao X.[Effects of fosinopril and losartan on the expression of Toll- like receptor 4 in renal tubular epithelia cells]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2008;33(10):958-965.
29.
Xie Z., Pimental DR, Lohan S., et al. Regulation of angiotensin IIstimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species. J Cell Physiol . 2001;188(1): 132-138.
30.
Xie Z., Singh M., Singh K.ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. J Cell Physiol. 2004; 198(3):399-407.
31.
Zhang YENon-Smad pathways in TGF-beta signaling. Cell Res.2009;19(1):128-139.
32.
Nakamura A. , Yoshida K., Takeda S., Dohi N., Ikeda S.Progression of dystrophic features and activation of mitogen-activated protein kinases and calcineurin by physical exercise, in hearts of mdx mice. FEBS Lett. 2002;520(1-3):18-24.
33.
Townsend D. , Yasuda S., Li S., Chamberlain JS, Metzger JMEmergent dilated cardiomyopathy caused by targeted repair of dystrophic skeletal muscle. Mol Ther. 2008;16(5):832-835.
