title: Dystrophin-deficient cardiomyopathy in mouse: expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart.
abstract: Duchenne muscular dystrophy (DMD; dystrophin-deficiency) causes dilated cardiomyopathy in the second decade of life in affected males. We studied the dystrophin-deficient mouse heart (mdx) using high-frequency echocardiography, histomorphometry, and gene expression profiling. Heart dysfunction was prominent at 9-10months of age and showed significantly increased LV internal diameter (end systole) and decreased posterior wall thickness. This cardiomyopathy was associated with a 30% decrease in shortening fraction. Histologically, there was a 10-fold increase in connective tissue volume (fibrosis). mRNA profiling with RT-PCR validation showed activation of key pro-fibrotic genes, including Nox4 and Lox. The Nox gene family expression differed in mdx heart and skeletal muscle, where Nox2 was specifically induced in skeletal muscle while Nox4 was specifically induced in heart. This is the first report of an altered profibrotic gene expression profile in cardiac tissue of dystrophic mice showing echocardiographic evidence of cardiomyopathy.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA. cspurney@cnmc.org
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
authors.forename: Susan
authors.initials: S
authors.lastname: Knoblach
authors.forename: Emidio E
authors.initials: EE
authors.lastname: Pistilli
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Martin
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D004452:Echocardiography; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018754:Ventricular Dysfunction / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism
chemical_list: D016189:Dystrophin; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; C077112:Lox protein, mouse; D008249:Protein-Lysine 6-Oxidase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse