TY - JOUR
T1 - 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
AU - Laeremans, Hilde
AU - Hackeng, Tilman M.
AU - van Zandvoort, Marc A. M. J.
AU - Thijssen, Victor L. J. L.
AU - Janssen, Ben J. A.
AU - Ottenheijm, Harry C. J.
AU - Smits, Jos F. M.
AU - Blankesteijn, W. Matthijs
PY - 2011/10/11
Y1 - 2011/10/11
N2 - 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. (Circulation. 2011; 124: 1626-1635.)
AB - 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. (Circulation. 2011; 124: 1626-1635.)
KW - heart failure
KW - myocardial infarction
KW - myofibroblasts
KW - pharmacology
KW - receptor blocker
KW - Wnt/frizzled pathway
U2 - 10.1161/CIRCULATIONAHA.110.976969
DO - 10.1161/CIRCULATIONAHA.110.976969
M3 - Article
C2 - 21931076
SN - 0009-7322
VL - 124
SP - 1626-U107
JO - Circulation
JF - Circulation
IS - 15
ER -