Submitted on September 7, 2007
Accepted on October 30, 2007
Caveolin-1 and caveolin-3 form hetero-oligomeric complexes in atrial cardiac myocytes which are required for doxorubicin-induced apoptosis
Daniela Volonte1, Charles F. McTiernan2, Marek Drab3, Michael Kasper4, and Ferruccio Galbiati1*
1 Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
2 Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
3 Max-Planck Institute, Berlin, Germany
4 Institute of Anatomy, University of Technology, Dresden, Germany
* To whom correspondence should be addressed. E-mail: feg5{at}pitt.edu.
Caveolae are 50-100 nm invaginations of the plasma membrane. Caveolins are the structural protein components of caveolar membranes. The caveolin gene family is composed of three members: caveolin-1, caveolin-2, and caveolin-3. Caveolin-1 and caveolin-2 are co-expressed in many cell types, including adipocytes, endothelial cells, epithelial cells, and fibroblasts. In contrast, caveolin-3 expression is essentially restricted to skeletal and smooth muscle cells, as well as cardiac myocytes, which express both caveolin-2 and caveolin-3. While the interaction between caveolin-1 and caveolin-2 has been previously documented, the reciprocal interaction between endogenous caveolin-1 and caveolin-3 and their functional role in cell types expressing both isoforms has yet to be identified. Here, we demonstrate for the first time that caveolin-1 and caveolin-3 are co-expressed in mouse and rat cardiac myocytes of the atria but not ventricles. We also found that caveolin-1 and caveolin-3 can interact and form hetero-oligomeric complexes in this cell type. Doxorubicin is an effective anticancer agent but its use is limited by the possible development of cardiotoxicity. Using caveolin-1 and caveolin-3 null mice, we show that both caveolin-1 and caveolin-3 expression are required for doxorubicin-induced apoptosis in the atria through activation of caspase 3. Taken together, these results bring new insight into the functional role of caveolae and suggest that caveolin-1/caveolin-3 hetero-oligomeric complexes may play a key role in chemotherapy-induced cardiotoxicity in the atria.
