Abstract 10595: Dapper-1 Depletion Inhibits Wnt5a Induced Cardiomyocyte Hypertrophy by Blocking the Wnt/PCP Pathway
Background: In recent years a growing body of evidence suggests the implication of Wnt signaling in cardiac diseases. While this pathway is quiescent in adult hearts activation occurs upon pathological stress. We have previously demonstrated that cardiac specific over-expression of the Wnt component Dapper-1 (Dpr1) activates canonical Wnt signaling and induces cardiac remodeling in a transgenic mouse model. Here, we focus on the functional role of Dpr1 in cardiomyocyte hypertrophy mediated by non-canonical Wnt signaling and the contribution of the non-canonical Wnt branches to the cardiomyopathic phenotype of Dpr1 transgenic mice.
Results: Neither in hearts of Dpr1 transgenic mice nor in Dpr1 over-expressed isolated cardiomyocytes we observed activation of non-canonical Wnt pathways demonstrating that Dpr1 does not activate the non-canonical Wnt branches and that cardiac hypertrophy in Dpr1 transgenic mice is a result of specific canonical/β-catenin signaling transduction. However, activation of non-canonical Wnt signaling by Wnt5a stimulates protein synthesis (+18 ± 3%, p<0,01 vs. unstimulated cells) and enlargement of cardiomyocyte surface area (+ 27% ± 5%, p<0,001 vs. unstimulated cells) and these hypertrophic features were completely inhibited in Dpr1 depleted cells. On molecular levels we observed inhibition of the non-canonical Wnt/PCP pathway in Dpr1 depleted cardiomyocytes denoted by reduction of JNK and c-jun phosphorylation. In addition, Wnt5a induced activation of JNK was blocked all indicating that Dpr1 is essential for Wnt/PCP pathway activation and non-canonical Wnt signaling mediated cardiomyocyte hypertrophy. Upstream of JNK a robust increase in protein levels of the Wnt/PCP trans-membrane receptor Vangl2 was observed (+150% ± 7%, p<0.05 vs. control cells) coincident with an enrichment of Vangl2 in perinuclear located vesicles suggesting that Dpr1 knockdown inhibits Vangl2 membrane carriage.
Conclusion: In cardiomyocytes Dpr1 is essential for execution of the Wnt/PCP pathway and regulates the Vangl2/JNK axis. Depletion of Dpr1 inhibits non-canonical Wnt signaling induced cardiomyocyte hypertrophy by blocking Wnt/PCP signaling and provides a novel target for research activities in the field of cardiac diseases.
- © 2013 by American Heart Association, Inc.