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

被引:308
作者
Ling, Haiyun [1 ]
Zhang, Tong [1 ]
Pereira, Laetitia [2 ]
Means, Christopher Kable [1 ]
Cheng, Hongqiang [3 ]
Gu, Yusu [3 ]
Dalton, Nancy D. [3 ]
Peterson, Kirk L. [3 ]
Chen, Ju [3 ]
Bers, Donald [2 ]
Brown, Joan Heller [1 ]
机构
[1] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
[2] UCD, Dept Pharmacol, Davis, CA USA
[3] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
关键词
DEPENDENT PROTEIN-KINASE; CALCIUM-RELEASE CHANNEL; RYANODINE RECEPTOR PHOSPHORYLATION; NUCLEAR DELTA(B) ISOFORM; FACTOR GENE-EXPRESSION; VENTRICULAR MYOCYTES; SARCOPLASMIC-RETICULUM; INHIBITION PROTECTS; IN-VIVO; DILATED CARDIOMYOPATHY;
D O I
10.1172/JCI38022
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Ca2+/calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKII delta, 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, HDACS phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKII delta 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 IP(3)R2 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 CaMKII delta contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca2+ leak and that attenuating CaMKII delta activation can limit the progression to heart failure.
引用
收藏
页码:1230 / 1240
页数:11
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