Transforming growth factor type-β inhibits Mas receptor expression in fibroblasts but not in myoblasts or differentiated myotubes; Relevance to fibrosis associated to muscular dystrophies

Item Type:	Article
Title:	Transforming growth factor type-β inhibits Mas receptor expression in fibroblasts but not in myoblasts or differentiated myotubes; Relevance to fibrosis associated to muscular dystrophies
Creators Name:	Cofre, C. and Acuna, M.J. and Contreras, O. and Morales, M.G. and Riquelme, C. and Bader, M. and Santos, R. and Cabello-Verrugio, C. and Brandan, E.
Abstract:	Duchenne muscular dystrophy is a genetic disorder characterized by myofiber degeneration, muscle weakness, and increased fibrosis. Transforming growth factor type-{beta} (TGF-{beta}), a central mediator of fibrosis, is upregulated in fibrotic diseases. Angiotensin-(1-7) [Ang-(1-7)] is a peptide with actions that oppose those of angiotensin-II (Ang II). Ang-(1-7) effects are mediated by the Mas receptor. Treatment with Ang-(1-7) produce positive effects in the mdx mouse, normalizing skeletal muscle architecture, decreasing local fibrosis, and fibroblasts, and improving muscle function. Mdx mice deficient for the Mas receptor showed the opposite effects. To identify the cell type(s) responsible for Mas receptor expression, and to characterize whether profibrotic effectors had any effect on its expression, we determined the effect of profibrotic agents on Mas expression. TGF-{beta}, but not connective tissue growth factor or Ang-II, reduced the expression of Mas receptor in fibroblasts isolated from skeletal muscle cells and fibroblasts from two established cell lines. In contrast, no effects were observed in myoblasts and differentiated myotubes. This inhibition was mediated by the Smad-dependent (canonical) and the PI3K and MEK1/2 (noncanonical) TGF-{beta} signaling pathways. When both canonical and noncanonical inhibitors of the TGF-{beta}-dependent pathways were added together, the inhibitory effect of TGF-{beta} on Mas expression was lost. The decrease in Mas receptor induced by TGF-{beta} in fibroblasts reduced the Ang-(1-7) mediated stimulation of phosphorylation of AKT pathway proteins. These results suggest that reduction of Mas receptor in fibroblasts, by TGF-{beta}, could increase the fibrotic phenotype observed in dystrophic skeletal muscle decreasing the beneficial effect of Ang-(1-7).
Keywords:	Skeletal Muscular Dystrophies, Mas Receptor, Fibrosis, TGF-{beta}, Fibroblasts, Muscle Cells, Animals, Mice
Source:	BioFactors
ISSN:	0951-6433
Publisher:	Wiley-Blackwell
Volume:	41
Number:	2
Page Range:	111-120
Date:	March 2015
Additional Information:	Erratum in: BioFactors 41(3): 209.
Official Publication:	https://doi.org/10.1002/biof.1208
PubMed:	View item in PubMed

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