Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice

Haiyun Ling, Tong Zhang, Laetitia Pereira, Christopher Kable Means, Hongqiang Cheng, Yusu Gu, Nancy D. Dalton, Kirk L. Peterson, Ju Chen, Donald M Bers, Joan Heller Brown

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Abstract

Ca2+/calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIδ, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIδ deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP3R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca2+ spark frequency only in WT mice. We suggest that CaMKIIδ contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca2+ leak and that attenuating CaMKIIδ activation can limit the progression to heart failure.

Original languageEnglish (US)
Pages (from-to)1230-1240
Number of pages11
JournalJournal of Clinical Investigation
Volume119
Issue number5
DOIs
StatePublished - May 1 2009

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ASJC Scopus subject areas

  • Medicine(all)

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Ling, H., Zhang, T., Pereira, L., Means, C. K., Cheng, H., Gu, Y., Dalton, N. D., Peterson, K. L., Chen, J., Bers, D. M., & Brown, J. H. (2009). Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. Journal of Clinical Investigation, 119(5), 1230-1240. https://doi.org/10.1172/JCI38022