Background-The molecular pathways that control the wound healing after myocardial infarction (MI) are not completely elucidated. One of these pathways is the Wnt/Frizzled pathway. In this study, we evaluated Frizzled as a novel therapeutic target for MI. These Frizzled proteins act as receptors for Wnt proteins and were previously shown to be expressed in the healing infarct. Methods and Results-Wnt/Frizzled signaling has been studied for decades, but synthetic ligands that interfere with the interaction between Wnts and Frizzled have not been described to date. Here we report the selection of 3 peptides derived from regions of high homology between Wnt3a and Wnt5a that act as antagonists for Frizzled proteins. UM206, the peptide with the highest affinity, antagonized the effect of Wnt3a and Wnt5a in different in vitro assays. Administration of UM206 to mice for 5 weeks, starting immediately after the induction of MI, reduced infarct expansion and increased the numbers of capillaries and myofibroblasts in the infarct area. Moreover, heart failure development was inhibited by this therapy. Key Words: heart failure Ⅲ myocardial infarction Ⅲ myofibroblasts Ⅲ pharmacology Ⅲ receptor blocker Ⅲ Wnt/frizzled pathway T he importance of Wnt signaling in developmental processes like cell proliferation, differentiation, and migration has been recognized for decades. 1,2 Wnt signaling has also been implicated in several diseases including cancer. 3,4 Although less well studied, there is growing evidence for a role of Wnt signaling in cardiovascular diseases, particularly in the remodeling that takes place in response to myocardial infarction (MI). [5][6][7][8] The underlying mechanism of Wnt signaling in cardiovascular diseases, however, is fundamentally different from that in, for example, colon cancer, in which mutations in the downstream signaling pathway lead to uncontrolled signaling and contribute to cell proliferation in the primary tumor. In cardiovascular diseases, no such mutations have been found to date. Instead, the increased expression of components of the Wnt signaling pathway suggests an activation rather than a disorder of the pathway. 7,8 Conclusions-Blocking Clinical Perspective on p 1635The involvement of Wnt signaling in multiple disease processes has fueled an intensive search for compounds that can modulate the activity of this pathway. 7,9 -11 The major focus of this research has been on the signal transduction pathway where ␤-catenin acts as a second messenger. The degradation of ␤-catenin is controlled by a complex containing casein kinase I, glycogen synthase kinase 3␤, axin, and adenomatous polyposis coli gene product. 4 Several wellknown compounds can attenuate Wnt signaling, including LiCl, vitamins A and D, and nonsteroidal anti-inflammatory drugs. 10 Moreover, novel drugs that inhibit glycogen synthase 1626by guest on March 28, 2012 http://circ.ahajournals.org/ Downloaded from kinase 3␤ or intervene in the interaction of ␤-catenin and T-cell factor/lymphoid enhancer factor have been descri...

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Myogenic differentiation involves myoblast fusion and induction of muscle-specific gene expression, which are both stimulated by pharmacological (LiCl), genetic, or IGF-I-mediated GSK-3β inactivation. To assess whether stimulation of myogenic differentiation is common to ligand-mediated GSK-3β inactivation, myoblast fusion and muscle-specific gene expression were investigated in response to Wnt-3a. Moreover, crosstalk between IGF-I/GSK-3β/NFATc3 and Wnt/GSK-3β/β-catenin signaling was assessed. While both Wnt-3a and LiCl promoted myoblast fusion, muscle-specific gene expression was increased by LiCl, but not by Wnt-3a or β-catenin over-expression. Furthermore, LiCl and IGF-I, but not Wnt-3a, increased NFATc3 transcriptional activity. In contrast, β-catenin-dependent transcriptional activity was increased by Wnt-3a and LiCl, but not IGF-I. These results for the first time reveal a segregated regulation of myoblast fusion and muscle-specific gene expression following stimulation of myogenic differentiation in response to distinct ligand-specific signaling routes of GSK-3β inactivation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-010-0467-7) contains supplementary material, which is available to authorized users.

The results indicate that myofibroblast migration and differentiation, but not proliferation, can be modulated by interventions in Wnt/Fzd signalling. Therefore, Wnt/Fzd signalling may serve as a novel therapeutic target to ameliorate wound healing after MI.