Heart Failure Blocking of Frizzled Signaling With a Homologous Peptide Fragment of Wnt3a/Wnt5a Reduces Infarct Expansion and Prevents the Development of Heart Failure After Myocardial Infarction

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. Conclusions—Blocking of Frizzled signaling reduces infarct expansion and preserves cardiac function after MI. Our findings underscore the potential of Frizzled receptors as a target for pharmacotherapy of cardiac remodeling after MI. 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– 8 The underlying mechanism of Wnt signal-ing 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 The 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. …