title: Dapper-1 induces myocardial remodeling through activation of canonical Wnt signaling in cardiomyocytes.
abstract: Heart failure has an increasing contribution to cardiovascular disease burden and is governed by the myocardial remodeling process. The contribution of Wnt signaling to cardiac remodeling has recently drawn significant attention. Here, we report that upregulation of Dapper-1 in a transgenic mouse model activates the canonical/β-catenin-dependent Wnt pathway through dishevelled-2. These mice exhibited increased heart weight/tibia length ratio, myocyte cross-sectional area, and upregulation of hypertrophic marker genes compared with wild-type mice. Furthermore, impairment of left ventricular systolic and diastolic function was observed in all indicating features of myocardial remodeling. Depletion of Dapper-1 and dishevelled-2 in cardiomyocytes demonstrated that Dapper-1 functions upstream of dishevelled-2 and that activity of both Dapper-1 and dishevelled-2 is essential for activating canonical Wnt signaling. Moreover, Dapper-1 depletion alleviated Wnt3a- and phenylephrine-induced cardiomyocyte hypertrophy. These observations provide evidence that Dapper-1-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.
authors.affiliation: Department of Cardiology, Angiology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Hagenmueller
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Riffel
authors.forename: Elmar
authors.initials: E
authors.lastname: Bernhold
authors.forename: Jingjing
authors.initials: J
authors.lastname: Fan
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Marco
authors.initials: M
authors.lastname: Ochs
authors.forename: Herbert
authors.initials: H
authors.lastname: Steinbeisser
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Hardt
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins; D051381:Rats; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C508545:frodo protein, mouse
keywords: Wnt signaling pathway; cardiac remodeling, ventricular; transgenic mice