title: Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2).
abstract: The renin-angiotensin system (RAS), through angiotensin II and the angiotensin-converting enzyme (ACE), is involved in the genesis and progression of fibrotic diseases characterized by the replacement of normal tissue by an accumulation of an extracellular matrix (ECM). Duchenne muscular dystrophy (DMD) presents fibrosis and a decrease in muscle strength produced by chronic damage. The mdx mouse is a murine model of DMD and develops the same characteristics as dystrophic patients when subjected to chronic exercise. The connective tissue growth factor (CTGF/CCN2) and transforming growth factor type beta (TGF-β), which are overexpressed in muscular dystrophies, play a major role in many progressive scarring conditions. We have tested the hypothesis that ACE inhibition decreases fibrosis in dystrophic skeletal muscle by treatment of mdx mice with the ACE inhibitor enalapril. Both sedentary and exercised mdx mice treated with enalapril showed improvement in gastrocnemius muscle strength explained by a reduction in both muscle damage and ECM accumulation. ACE inhibition decreased CTGF expression in sedentary or exercised mdx mice and diminished CTGF-induced pro-fibrotic activity in a model of CTGF overexpression by adenoviral infection. Enalapril did not have an effect on TGF-β1 expression or its signaling activity in sedentary or exercised dystrophic mice. Thus, ACE inhibition might improve muscle strength and decrease fibrosis by diminishing specifically CTGF expression and activity without affecting TGF-β1 signaling. Our data provide insights into the pathogenic events in dystrophic muscle. We propose ACE as a target for developing therapies for DMD and related diseases.
authors.affiliation: Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas & Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Morales
authors.forename: Daniel
authors.initials: D
authors.lastname: Cabrera
authors.forename: Carlos
authors.initials: C
authors.lastname: Céspedes
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Vio
authors.forename: Yaneisi
authors.initials: Y
authors.lastname: Vazquez
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
authors.forename: Claudio
authors.initials: C
authors.lastname: Cabello-Verrugio
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D004656:Enalapril / Q000494:pharmacology; D005355:Fibrosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010805:Physical Conditioning, Animal; D012084:Renin-Angiotensin System; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; C526318:CCN2 protein, mouse; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A