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

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65 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)891-899
Number of pages9
JournalCirculation
Volume122
Issue number9
DOIs
Publication statusPublished - Aug 31 2010

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Toko, H., Takahashi, H., Kayama, Y., Oka, T., Minamino, T., Okada, S., Morimoto, S., Zhan, D. Y., Terasaki, F., Anderson, M. E., Inoue, M., Yao, A., Nagai, R., Kitaura, Y., Sasaguri, T., & Komuro, I. (2010). Ca2+/calmodulin-dependent kinase IIδ causes heart failure by accumulation of p53 in dilated cardiomyopathy. Circulation, 122(9), 891-899. https://doi.org/10.1161/CIRCULATIONAHA.109.935296