title: 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.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, 50 Universiteitssingel, 6229ER Maastricht/PO Box 616, 6200MD Maastricht, Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Laeremans
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.forename: Marc A M J
authors.initials: MA
authors.lastname: van Zandvoort
authors.forename: Victor L J L
authors.initials: VL
authors.lastname: Thijssen
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Harry C J
authors.initials: HC
authors.lastname: Ottenheijm
authors.forename: Jos F M
authors.initials: JF
authors.lastname: Smits
authors.forename: W Matthijs
authors.initials: WM
authors.lastname: Blankesteijn
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000187:drug effects; D051157:Frizzled Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D020257:Ventricular Remodeling / Q000187:drug effects; D060509:Wnt3A Protein / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; C489743:Fzd2 protein, mouse; D010446:Peptide Fragments; D060509:Wnt3A Protein