Calmodulin kinase II inhibition protects against structural heart disease

Rong Zhang, Michelle S C Khoo, Yuejin Wu, Yingbo Yang, Chad E. Grueter, Gemin Ni, Edward E. Price, William Thiel, Silvia Guatimosim, Long Sheng Song, Ernest C. Madu, Anisha N. Shah, Tatiana A. Vishnivetskaya, James B. Atkinson, Vsevolod V. Gurevich, Guy Salama, W. J. Lederer, Roger J. Colbran, Mark E. Anderson

Research output: Contribution to journalArticle

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Abstract

β-Adrenergic receptor (βAR) stimulation increases cytosolic Ca2+ to physiologically augment cardiac contraction, whereas excessive βAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca2+-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the βAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in βAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive βAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and βAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to βAR signaling.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalNature Medicine
Volume11
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Zhang, R., Khoo, M. S. C., Wu, Y., Yang, Y., Grueter, C. E., Ni, G., Price, E. E., Thiel, W., Guatimosim, S., Song, L. S., Madu, E. C., Shah, A. N., Vishnivetskaya, T. A., Atkinson, J. B., Gurevich, V. V., Salama, G., Lederer, W. J., Colbran, R. J., & Anderson, M. E. (2005). Calmodulin kinase II inhibition protects against structural heart disease. Nature Medicine, 11(4), 409-417. https://doi.org/10.1038/nm1215