Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 5, Pages 1237-1249Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt514
Keywords
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Funding
- CARE PFB [12/2007]
- FONDECYT [1110426]
- CONICYT [AT-2410061]
- Fundacion Chilena para Biologia Celular [Proyecto MF-100]
- MDA [SAF2012-38547, PLE2009-0124]
- AFM
- ICREA Funding Source: Custom
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Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease, and is characterized by the lack of dystrophin, muscle wasting, increased transforming growth factor (TGF)-beta Smad-dependent signalling and fibrosis. Acting via the Mas receptor, angiotensin-1-7 [Ang-(1-7)], is part of the renin-angiotensin system, with the opposite effect to that of angiotensin II. We hypothesized that the Ang-(1-7)/Mas receptor axis might protect chronically damaged tissues as in skeletal muscle of the DMD mouse model mdx. Infusion or oral administration of Ang-(1-7) in mdx mice normalized skeletal muscle architecture, decreased local fibrosis and improved muscle function in vitro and in vivo. These positive effects were mediated by the inhibition of TGF-beta Smad signalling, which in turn led to reduction of the pro-fibrotic microRNA miR-21 concomitant with a reduction in the number of TCF4 expressing fibroblasts. Mdx mice infused with Mas antagonist (A-779) and mdx deficient for the Mas receptor showed highly deteriorated muscular architecture, increased fibrosis and TGF-beta signalling with diminished muscle strength. These results suggest that this novel compound Ang-(1-7) might be used to improve quality of life and delay death in individuals with DMD and this drug should be investigated in further pre-clinical trials.
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