title: Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.
abstract: 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.
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Haruhiro
authors: H
authors: Toko
authors: Hidehisa
authors: H
authors: Takahashi
authors: Yosuke
authors: Y
authors: Kayama
authors: Toru
authors: T
authors: Oka
authors: Tohru
authors: T
authors: Minamino
authors: Sho
authors: S
authors: Okada
authors: Sachio
authors: S
authors: Morimoto
authors: Dong-Yun
authors: DY
authors: Zhan
authors: Fumio
authors: F
authors: Terasaki
authors: Mark E
authors: ME
authors: Anderson
authors: Masashi
authors: M
authors: Inoue
authors: Atsushi
authors: A
authors: Yao
authors: Ryozo
authors: R
authors: Nagai
authors: Yasushi
authors: Y
authors: Kitaura
authors: Toshiyuki
authors: T
authors: Sasaguri
authors: Issei
authors: I
authors: Komuro
mesh_terms: 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
chemical_list: 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