TY - JOUR
T1 - Ca2+/calmodulin-dependent kinase IIδ causes heart failure by accumulation of p53 in dilated cardiomyopathy
AU - Toko, Haruhiro
AU - Takahashi, Hidehisa
AU - Kayama, Yosuke
AU - Oka, Toru
AU - Minamino, Tohru
AU - Okada, Sho
AU - Morimoto, Sachio
AU - Zhan, Dong Yun
AU - Terasaki, Fumio
AU - Anderson, Mark E.
AU - Inoue, Masashi
AU - Yao, Atsushi
AU - Nagai, Ryozo
AU - Kitaura, Yasushi
AU - Sasaguri, Toshiyuki
AU - Komuro, Issei
PY - 2010/8/31
Y1 - 2010/8/31
N2 - 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. Methods and Results: We established the mouse model of DCM by expressing a mutated cardiac α-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 IIδ (CaMKIIδ). The inhibition of CaMKIIδ prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function. CONCLUSION-: CaMKIIδ 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.
AB - 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. Methods and Results: We established the mouse model of DCM by expressing a mutated cardiac α-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 IIδ (CaMKIIδ). The inhibition of CaMKIIδ prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function. CONCLUSION-: CaMKIIδ 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.
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U2 - 10.1161/CIRCULATIONAHA.109.935296
DO - 10.1161/CIRCULATIONAHA.109.935296
M3 - Article
C2 - 20713897
AN - SCOPUS:77956385759
SN - 0009-7322
VL - 122
SP - 891
EP - 899
JO - Circulation
JF - Circulation
IS - 9
ER -