Clin Res Cardiol 101, Suppl 1, April 2012

P992 - Dapper-1, a novel activator of Wnt signaling in cardiomyocytes, induces cardiac hypertrophy and impairs left ventricular function
M. Hagenmüller1, J. Riffel1, E. Bernhold1, H. A. Katus1, S. Hardt1
1Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg;
Rationale: The contribution of the Wnt signaling pathway 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.
Objective: We investigated the role of Dpr1 in myocardial function and Wnt signaling transduction.
Methods and Results: We established a transgenic mouse model with cardiac-specific over-expression of Dpr1. Dpr1-tg mice exhibited an increased heart weight:tibia length ratio, augmentation of the myocyte cross-sectional area and up-regulation of hypertrophy marker genes compared to WT mice indicating onset of myocardial remodeling. Pressure-volume loop analysis revealed impairment of left ventricular systolic and diastolic function. On the molecular level, we noted up-regulation of Dvl2 protein expression and activation of the canonical/β-catenin-dependent Wnt pathway via accumulation of β-catenin and expression of its target genes. Dpr1 specific siRNA mediated knockdown experiments in cultured cardiomyocytes demonstrated that Dpr1 is essential for activating canonical Wnt signaling. Furthermore, depletion of Dpr1 rescued Wnt3a- and phenylephrine-induced cardiomyocyte hypertrophy.
Conclusions: These observations provide evidence that Dpr1-mediated activation of canonical Wnt signaling is sufficient to induce cardiomyocyte hypertrophy. Inhibition of this pathway may thus serve as a novel therapeutic strategy for impeding cardiac hypertrophy.
Clin Res Cardiol 101, Suppl 1, April 2012
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-012-1100-6