Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice
Haiyun Ling, … , Donald Bers, Joan Heller Brown
Haiyun Ling, … , Donald Bers, Joan Heller Brown
Published April 20, 2009
Citation Information: J Clin Invest. 2009;119(5):1230-1240. https://doi.org/10.1172/JCI38022.
View: Text | PDF | Erratum
Research Article

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

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.

Authors

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

×

Figure 4

Effects of CaMKIIδ deletion on the development of cardiac hypertrophy and heart failure after 6-week TAC.

Options: View larger image (or click on image) Download as PowerPoint
Effects of CaMKIIδ deletion on the development of cardiac hypertrophy an...
Shown are averaged echocardiographic parameters and percent survival in WT and CaMKIIδ-deficient mice at different time points after TAC. Data are mean ± SEM of values from 12–18 mice, unless otherwise indicated. (A) Hypertrophic responses. (B) Decompensation to heart failure. Percent survival in response to TAC is plotted as a Kaplan-Meier curve (P = 0.08, WT versus KO). *P < 0.05, **P < 0.01, ***P < 0.001 versus pre-echocardiography; #P < 0.05, ##P < 0.01 versus WT.