Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype.
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.
Aravamudan
Bharathi
B
Department of Pharmacology, University of Pittsburgh School of Medicine, PA 15261, USA.
Volonte
Daniela
D
Ramani
Ravi
R
Gursoy
Erdal
E
Lisanti
Michael P
MP
London
Barry
B
Galbiati
Ferruccio
F
D000818:Animals; D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1; D051244:Caveolin 3; D022461:Caveolins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D004562:Electrocardiography; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; C495548:Cav3 protein, mouse; D051242:Caveolin 1; D051244:Caveolin 3; D022461:Caveolins; D016189:Dystrophin; D019001:Nitric Oxide Synthase