Critical role of nuclear calcium/calmodulin-dependent protein kinase IIdeltaB in cardiomyocyte survival in cardiomyopathy.
Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in cardiac contractility and heart disease. However, the specific role of alternatively spliced variants of CaMKII in cardiac disease and apoptosis remains poorly explored. Here we report that the deltaB subunit of CaMKII (CaMKIIdeltaB), which is the predominant nuclear isoform of calcium/calmodulin-dependent protein kinases in heart muscle, acts as an anti-apoptotic factor and is a novel target of the antineoplastic and cardiomyopathic drug doxorubicin (Dox (adriamycin)). Hearts of rats that develop cardiomyopathy following chronic treatment with Dox also show down-regulation of CaMKIIdeltaB mRNA, which correlates with decreased cardiac function in vivo, reduced expression of sarcomeric proteins, and increased tissue damage associated with Dox cardiotoxicity. Overexpression of CaMKIIdeltaB in primary cardiac cells inhibits Dox-mediated apoptosis and prevents the loss of the anti-apoptotic protein Bcl-2. Specific silencing of CaMKIIdeltaB by small interfering RNA prevents the formation of organized sarcomeres and decreases the expression of Bcl-2, which all mimic the effect of Dox. CaMKIIdeltaB is required for GATA-4-mediated co-activation and binding to the Bcl-2 promoter. These results reveal that CaMKIIdeltaB plays an essential role in cardiomyocyte survival and provide a mechanism for the protective role of CaMKIIdeltaB. These results suggest that selective targeting of CaMKII in the nuclear compartment might represent a strategy to regulate cardiac apoptosis and to reduce Dox-mediated cardiotoxicity.
Little
Gillian H
GH
Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Saw
Aman
A
Bai
Yan
Y
Dow
Joan
J
Marjoram
Paul
P
Simkhovich
Boris
B
Leeka
Justin
J
Kedes
Larry
L
Kloner
Robert A
RA
Poizat
Coralie
C
D000818:Animals; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism / Q000502:physiology*; D009202:Cardiomyopathies / Q000201:enzymology* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D020868:Gene Silencing; D032383:Myocytes, Cardiac / Q000201:enzymology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D019253:Proto-Oncogene Proteins c-bcl-2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2