Ca2+/calmodulin-dependent kinase IIδ causes heart failure by accumulation of p53 in dilated cardiomyopathy

Haruhiro Toko, Hidehisa Takahashi, Yosuke Kayama, Toru Oka, Tohru Minamino, Sho Okada, Sachio Morimoto, Dong Yun Zhan, Fumio Terasaki, Mark E. Anderson, Masashi Inoue, Atsushi Yao, Ryozo Nagai, Yasushi Kitaura, Toshiyuki Sasaguri, Issei Komuro

研究成果: Contribution to journalArticle査読

70 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)891-899
ページ数9
ジャーナルCirculation
122
9
DOI
出版ステータス出版済み - 8 31 2010

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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