title: UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine.
abstract: Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (-41±10%), whereas infarct mass remained stable in the Control-MI group (+3±17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53±0.43% vs 3.38±0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling.
authors.affiliation: Department of Cardiology, Division of Experimental Cardiology, Thoraxcenter Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: André
authors.initials: A
authors.lastname: Uitterdijk
authors.affiliation: Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Kevin C M
authors.initials: KC
authors.lastname: Hermans
authors.affiliation: Department of Cardiology, Division of Experimental Cardiology, Thoraxcenter Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Daphne P M
authors.initials: DP
authors.lastname: de Wijs-Meijler
authors.affiliation: Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Evangelos P
authors.initials: EP
authors.lastname: Daskalopoulos
authors.affiliation: Department of Neonatology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Irwin K
authors.initials: IK
authors.lastname: Reiss
authors.affiliation: Department of Cardiology, Division of Experimental Cardiology, Thoraxcenter Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.affiliation: Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Matthijs Blankesteijn
authors.affiliation: Department of Cardiology, Division of Experimental Cardiology, Thoraxcenter Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
mesh_terms: D000818:Animals; D051157:Frizzled Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology*; D013552:Swine; D020257:Ventricular Remodeling; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins