Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.
BACKGROUND
Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown.


RESULTS
We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase IIdelta (CaMKIIdelta). The inhibition of CaMKIIdelta prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function.


CONCLUSIONS
CaMKIIdelta plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.
Toko
Haruhiro
H
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Takahashi
Hidehisa
H
Kayama
Yosuke
Y
Oka
Toru
T
Minamino
Tohru
T
Okada
Sho
S
Morimoto
Sachio
S
Zhan
Dong-Yun
DY
Terasaki
Fumio
F
Anderson
Mark E
ME
Inoue
Masashi
M
Yao
Atsushi
A
Nagai
Ryozo
R
Kitaura
Yasushi
Y
Sasaguri
Toshiyuki
T
Komuro
Issei
I
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000096926:Benzenesulfonamides
D000199:Actins; D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C072105:KN 93; D000096926:Benzenesulfonamides; C517673:Camk2d protein, mouse