Abstract 15403: Dishevelled-Induced Cardiomyopathy is Rescued by Deletion of Calcium/Calmodulin-Dependent Protein Kinase II
Background: Our previous findings have shown that cardiac overexpression of Dishevelled 1 (Dvl-1) results in cardiomyopathy. Recently, growing lines of evidence document Calcium/calmodulin-dependent protein kinase II (CaMKII) as a pivotal participant in myocardial remodeling. Since CaMKII is a critical downstream target of Dvl-1, this study aims to elucidate the role of CaMKII in Dvl-1-induced cardiac remodeling.
Methods and Results: Dvl-1 transgenic (Dvl-1-Tg) mice were crossed with CaMKIIδγ knockout (CaMKIIδγ-KO) mice to generate Dvl-1-Tg mice with CaMKIIδγ-KO (DWC). Dvl-1-Tg mice suffered from heart failure (HF) and cardiac hypertrophy in early adulthood. By contrast, DWC mice displayed normal cardiac phenotype without hypertrophy and HF, assessed by echocardiography and hemodynamic measurement. CaMKIIδγ-KO in Dvl-1-Tg mice attenuated Dvl-1-Tg induced increase of heart weight/body weight ratio (Control 4.74±0.18, CaMKIIδγ-KO 4.88±0.19, Dvl-1-Tg 5.44±0.18, DWC 5.09±0.14; n>10, p<0.001), and blocked transcription of hypertrophic marker gene ANF. In addition, a blunted cardiac fibrosis was confirmed by picrosirius red staining. Using western blot, we observed robustly increased amount of phosphorylated histone deacetylase 4 (HDAC4), which was inhibited by CaMKIIδγ-KO in Dvl-1-Tg animals. In order to further confirm these observations, adenoviral Dvl-1 overexpression was used to stimulate cultured cardiomyocytes, causing up to 40% increase of cardiamyocyte size and 2-fold upregulation of ANF-expression. Addition of KN93, a CaMKII inhibitor, prevented myocyte hypertrophy. CaMKII antagonism also suppressed the phosphorylation/exit of HDAC4 from nucleus. Moreover, when cardiomyocytes treated with adenovirus encoding a phosphorylation-resistant HDAC4 mutant–HDAC4-S246,467,632A, Dvl-1 overexpression-evoked enhancement of ANF and cardiomyocyte size were completely reversed.
Conclusions: CaMKII functions as an important transducer of Dvl-1 in cardiac remodeling and pathogenesis of HF, which is mediated by phosphorylation of HDAC4. Therefore, our findings further support Wnt-signaling pathway to be an attractive therapeutic opportunity for prevention of cardiac remodeling and its progression to HF.
- © 2011 by American Heart Association, Inc.