Abstract 14238: Dapper-1 Induces Myocardial Remodeling Through Selective Activation of Canonical Wnt Signaling in Cardiomyocytes
Background: The contribution of Wnt signaling to cardiac remodeling has recently drawn significant attention. Dishevelled proteins (Dvl) are key modulators of canonical and non-canonical Wnt signaling. Dapper-1 (Dpr1) is a Dvl-modulating protein, which so far has been described as an antagonist of Dvl. In the remote area of rat myocardial infarction tissue robust over-expression of Dpr1 was present indicating its involvement in cardiac remodeling.
Methods and Results: To explore the role of Dpr1 in cardiomyocytes we generated a transgenic mouse model with cardiac restricted over-expression of Dpr1 (Dpr1-tg). Dpr1-tg mice exhibited increased heart weight / tibia length ratio, myocyte cross-sectional area and up-regulation of hypertrophic marker genes compared to wt mice. Furthermore, impairment of left ventricular systolic and diastolic function was observed all indicating onset of myocardial remodeling. On the molecular level, we noted up-regulation of Dvl2 accompanied by exclusive activation of the canonical/β-catenin-dependent Wnt pathway via accumulation of β-catenin, its translocation into the nucleus as well as robust expression of canonical Wnt target genes. Interestingly, non-canonical Wnt signaling remained quiescent. Specific siRNA depletion of Dpr1 and Dvl2 in cardiomyocytes demonstrated that Dpr1 functions upstream of Dvl2 and that activity of both Dpr1 and Dvl2 is essential for activating canonical Wnt signaling. Moreover, depletion of Dpr1 rescued Wnt3a- and phenylephrine-induced cardiomyocyte hypertrophy.
Conclusions: These observations provide evidence that Dpr1-mediated activation of canonical Wnt signaling is necessary and sufficient to induce cardiomyocyte hypertrophy. Inhibition of this pathway may thus serve as a novel therapeutic strategy for alleviating cardiac hypertrophy.
- © 2012 by American Heart Association, Inc.