title: Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium.
abstract: Null mutation of dystrophin causes the lethal pathology of Duchenne muscular dystrophy (DMD) in which there is progressive pathology of skeletal and cardiac muscles. A large proportion of DMD patient deaths are attributable to cardiac dysfunction associated with ventricular fibrosis, arrhythmias and conduction abnormalities, although the relationships between the dystrophin mutation and the cardiac defects are unknown. Here, we tested whether cardiac pathology in dystrophin-deficient mdx mice can be corrected by the elevated production of nitric oxide (NO) by the myocardium. Dystrophin-deficient mdx mice were produced in which there was myocardial expression of a neuronal nitric oxide synthase (nNOS) transgene. Expression of the transgene prevented the progressive ventricular fibrosis of mdx mice and greatly reduced myocarditis. Electrocardiographs (ECG) attained by radiotelemetry of freely ambulatory mice showed that mdx mice displayed cardiac abnormalities that are characteristic of DMD patients, including deep Q-waves, diminished S:R ratios, polyphasic R-waves and frequent premature ventricular contractions. All of these ECG abnormalities in mdx mice were improved or corrected by nNOS transgene expression. In addition, defects in mdx cardiac autonomic function, which were reflected by decreased heart rate variability, were significantly reduced by nNOS transgene expression. These findings indicate that increasing NO production by dystrophic hearts may have therapeutic value.
authors.affiliation: Department of Physiological Science, David Geffen School of Medicine, University of California, Los Angeles 90095, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Wehling-Henricks
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Roos
authors.forename: Bo
authors.initials: B
authors.lastname: Deng
authors.forename: James G
authors.initials: JG
authors.lastname: Tidball
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000503:physiopathology; D016189:Dystrophin / Q000235:genetics*; D004562:Electrocardiography; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D019076:Transgenes
chemical_list: D016189:Dystrophin; D009569:Nitric Oxide