Article

Intramuscular renin-angiotensin system is activated in human muscular dystrophy.

Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
Journal of the neurological sciences (impact factor: 2.32). 03/2009; 280(1-2):40-8. DOI:10.1016/j.jns.2009.01.020 pp.40-8
Source: PubMed

ABSTRACT To investigate the role of the muscular renin-angiotensin system (RAS) in human muscular dystrophy, we used immunohistochemistry and Western blotting to examine the cellular localization of angiotensin-converting enzyme (ACE), the angiotensin II type 1 receptor (AT1) and the angiotensin II type 2 receptor (AT2) in muscle biopsies from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and congenital muscular dystrophy (CMD). In normal muscle, ACE was expressed in vascular endothelial cells and neuromuscular junctions (NMJs), whereas AT1 was immunolocalized to the smooth muscle cells of blood vessels and intramuscular nerve twigs. AT2 was immunolocalized in the smooth muscle cells of blood vessels. These findings suggest that the RAS has a functional role in peripheral nerves and NMJs. ACE and AT1, but AT2 immunoreactivity were increased markedly in dystrophic muscle as compared to controls. ACE and the AT1 were strongly expressed in the cytoplasm and nuclei of regenerating muscle fibers, fibroblasts, and in macrophages infiltrating necrotic fibers. Double immunolabeling revealed that activated fibroblasts in the endomysium and perimysium of DMD and CMD muscle were positive for ACE and AT1. Triple immunolabeling demonstrated that transforming growth factor-beta1 (TGF-beta1) and ACE were colocalized on the cytoplasm of activated fibroblasts in dystrophic muscle. Furthermore, Western blotting showed increases in the expression of AT1 and TGF-beta1 protein in dystrophic muscle, which coincided with our immunohistochemical results. The overexpression of ACE and AT1 in dystrophic muscle would likely result in the increased production of Ang II, which may act on these cells in an autocrine manner via AT1. The activation of AT1 may induce fibrous tissue formation through overexpression of TGF-beta1, which potently activates fibrogenesis and suppresses regeneration. In conclusion, our results imply that the intramuscular RAS-TGF-beta1 pathway is activated in human muscular dystrophy and plays a role at least partly in the pathophysiology of this disease.

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Keywords

activated fibroblasts
 
Ang II
 
angiotensin II type 1 receptor
 
angiotensin II type 2 receptor
 
Becker muscular dystrophy
 
blood vessels
 
cellular localization
 
CMD muscle
 
dystrophic muscle
 
immunohistochemical results
 
intramuscular nerve twigs
 
intramuscular RAS-TGF-beta1 pathway
 
muscle biopsies
 
muscular renin-angiotensin system
 
normal muscle
 
smooth muscle cells
 
suppresses regeneration
 
transforming growth factor-beta1
 
vascular endothelial cells
 
Western blotting