title: Losartan, a therapeutic candidate in congenital muscular dystrophy: studies in the dy(2J) /dy(2J) mouse.
abstract: OBJECTIVE
  Lamininα2-deficient congenital muscular dystrophy type 1A (MDC1A) is a cureless disease associated with severe disability and shortened lifespan. Previous studies have shown reduced fibrosis and restored skeletal muscle remodeling following treatment with losartan, an angiotensin II type I receptor blocker. We therefore evaluated the effect of losartan treatment in the dy(2J) /dy(2J) mouse model of MDC1A.
  
  
  METHODS
  Homozygous dy(2J) /dy(2J) and control mice were treated with losartan or placebo for 12 weeks from 6 weeks of age. Outcome measures included hindlimb and forelimb muscle strength by Grip Strength Meter and quantitative muscle fibrosis parameters. Losartan's effects on transforming growth factor β (TGF-β) and mitogen-activated protein kinase (MAPK) signaling pathways were evaluated with Western blotting, immunofluorescence, and cytokine measurements.
  
  
  RESULTS
  Losartan treatment was associated with significant impressive improvement in muscle strength and amelioration of fibrosis. Administration of losartan inhibited TGF-β signaling pathway, resulting in decreased serum TGF-β1 level and reduced downstream phosphorylated (P) Smad2/3 proteins. Moreover, losartan activated Smad7 protein, a key negative regulator of TGF-β signaling. In addition, losartan treatment inhibited the MAPK cascade as shown by decreased expression of P-p38 MAPK, P-c-jun-N-terminal kinase, and P-extracellular signal-regulated kinases 1 and 2 in the treated mice.
  
  
  CONCLUSIONS
  Losartan, a commonly prescribed US Food and Drug Administration-approved medication for hypertension, demonstrated clinical improvement and amelioration of fibrosis in the dy(2J) /dy(2J) mouse model of MDC1A via TGF-β and MAPK signaling pathways. The results of this study support pursuing a clinical trial of losartan treatment in children with MDC1A.
authors.affiliation: Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Elbaz
authors.forename: Nurit
authors.initials: N
authors.lastname: Yanay
authors.forename: Shlomit
authors.initials: S
authors.lastname: Aga-Mizrachi
authors.forename: Zivia
authors.initials: Z
authors.lastname: Brunschwig
authors.forename: Ibaa
authors.initials: I
authors.lastname: Kassis
authors.forename: Keren
authors.initials: K
authors.lastname: Ettinger
authors.forename: Vivian
authors.initials: V
authors.lastname: Barak
authors.forename: Yoram
authors.initials: Y
authors.lastname: Nevo
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D007797:Laminin / Q000235:genetics; D019808:Losartan / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053580:Muscle Strength / Q000187:drug effects*; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007797:Laminin; C102645:laminin alpha 2; D019808:Losartan