Human Molecular Genetics Advance Access originally published online on September 9, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 21 2777-2788
DOI: 10.1093/hmg/ddg313
© 2003 Oxford University Press
Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype
1Department of Pharmacology and 2The Cardiovascular Institute, University of Pittsburgh School of Medicine,Pittsburgh, PA 15261, USA
Received June 14, 2003; Revised August 22, 2003; Accepted September 1, 2003
Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of caveolin-3 expression is fundamental for normal muscle functions. Since caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of caveolin-3 on cardiac structure and function by characterizing caveolin-3 transgenic mice. Our results indicate that overexpression of caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of caveolin-3 in the heart. Taken together, these results indicate that overexpression of caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.
* To whom correspondence should be addressed. Tel: +1 4126482047; Fax: +1 4126481945; E-mail: feg5{at}pitt.edu
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