Human Molecular Genetics Advance Access published online on May 25, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi197
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1 Department of Physiological Science, University of California at Los Angeles, Los Angeles, CA 90095
* To whom correspondence should be addressed. Null mutation of dystrophin causes the lethal pathology of Duchenne muscular dystrophy (DMD) in which there is progressive pathology of skeletal and cardiac muscle. 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 cardiac defects are unknown. Here, we tested whether cardiac pathology in dystrophin-deficient mdx mice can be corrected by elevated production of nitric oxide 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 that 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.
Received January 26, 2005
Revised April 18, 2005
Accepted May 17, 2005
Article
Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium
2 Department of Physiology, University of California at Los Angeles, Los Angeles, CA 90095
3 Molecular, Cellular and Integrative Physiology Program at the David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095
4 Department of Physiological Science, University of California at Los Angeles, Los Angeles, CA 90095; Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA 90095; Molecular, Cellular and Integrative Physiology Program at the David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095
James G. Tidball, E-mail: jtidball{at}physci.ucla.edu
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