PMID- 19602725
OWN - NLM
STAT- MEDLINE
DCOM- 20091102
LR  - 20220819
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 284
IP  - 37
DP  - 2009 Sep 11
TI  - Critical role of nuclear calcium/calmodulin-dependent protein kinase IIdeltaB in 
      cardiomyocyte survival in cardiomyopathy.
PG  - 24857-68
LID - 10.1074/jbc.M109.003186 [doi]
AB  - 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.
FAU - Little, Gillian H
AU  - Little GH
AD  - Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, 
      Keck School of Medicine, University of Southern California, Los Angeles, 
      California 90033, USA.
FAU - Saw, Aman
AU  - Saw A
FAU - Bai, Yan
AU  - Bai Y
FAU - Dow, Joan
AU  - Dow J
FAU - Marjoram, Paul
AU  - Marjoram P
FAU - Simkhovich, Boris
AU  - Simkhovich B
FAU - Leeka, Justin
AU  - Leeka J
FAU - Kedes, Larry
AU  - Kedes L
FAU - Kloner, Robert A
AU  - Kloner RA
FAU - Poizat, Coralie
AU  - Poizat C
LA  - eng
GR  - C06 CA62528-01/CA/NCI NIH HHS/United States
GR  - C06 CA062528/CA/NCI NIH HHS/United States
GR  - C06 RR10600-01/RR/NCRR NIH HHS/United States
GR  - C06 RR014514-01/RR/NCRR NIH HHS/United States
GR  - C06 RR014514/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090714
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism/*physiology
MH  - Cardiomyopathies/*enzymology/pathology
MH  - Cell Nucleus/*metabolism
MH  - Cell Survival
MH  - Down-Regulation
MH  - Female
MH  - Gene Expression Profiling
MH  - Gene Silencing
MH  - Myocytes, Cardiac/*enzymology
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Transfection
PMC - PMC2757189
EDAT- 2009/07/16 09:00
MHDA- 2009/11/03 06:00
PMCR- 2010/09/11
CRDT- 2009/07/16 09:00
PHST- 2009/07/16 09:00 [entrez]
PHST- 2009/07/16 09:00 [pubmed]
PHST- 2009/11/03 06:00 [medline]
PHST- 2010/09/11 00:00 [pmc-release]
AID - S0021-9258(20)30574-3 [pii]
AID - M109.003186 [pii]
AID - 10.1074/jbc.M109.003186 [doi]
PST - ppublish
SO  - J Biol Chem. 2009 Sep 11;284(37):24857-68. doi: 10.1074/jbc.M109.003186. Epub 
      2009 Jul 14.