Caveolin-1 and caveolin-3 form heterooligomeric complexes in atrial cardiac myocytes that are required for doxorubicin-induced apoptosis.
Caveolae are 50- to 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 coexpressed 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. While the interaction between caveolin-1 and caveolin-2 has been documented previously, the reciprocal interaction between endogenous caveolin-1 and caveolin-3 and their functional role in cell types expressing both isoforms have yet to be identified. Here we demonstrate for the first time that caveolin-1 and caveolin-3 are coexpressed 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 heterooligomeric 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. Together, these results bring new insight into the functional role of caveolae and suggest that caveolin-1/caveolin-3 heterooligomeric complexes may play a key role in chemotherapy-induced cardiotoxicity in the atria.
Volonte
Daniela
D
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
McTiernan
Charles F
CF
Drab
Marek
M
Kasper
Michael
M
Galbiati
Ferruccio
F
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D021941:Caveolae / Q000187:drug effects* / Q000378:metabolism; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051244:Caveolin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; C495541:Cav1 protein, mouse; C495537:Cav1 protein, rat; C495548:Cav3 protein, mouse; C495549:Cav3 protein, rat; D051242:Caveolin 1; D051244:Caveolin 3; D046912:Multiprotein Complexes; D004317:Doxorubicin; D053148:Caspase 3