title: Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling.
abstract: Wnt signaling plays an important role in developmental and stem cell biology. To test the hypothesis that temporary inhibition of Wnt signaling will enhance granulation tissue and promote angiogenesis in tissue repair, we employed a recently characterized small molecule Wnt inhibitor. Pyrvinium is an FDA-approved drug that we identified as a Wnt inhibitor in a chemical screen for small molecules that stabilize β-catenin and inhibit Axin degradation. Our subsequent characterization of pyrvinium has revealed that its critical cellular target in the Wnt pathway is Casein Kinase 1α. Daily administration of pyrvinium directly into polyvinyl alcohol (PVA) sponges implanted subcutaneously in mice generated better organized and vascularized granulation tissue; this compound also increased the proliferative index of the tissue within the sponges. To evaluate its effect in myocardial repair, we induced a myocardial infarction (MI) by coronary artery ligation and administered a single intramyocardial dose of pyrvinium. Mice were evaluated by echocardiography at 7 and 30 days post-MI and treatment; post mortem hearts were evaluated by histology at 30 days. Pyrvinium reduced adverse cardiac remodeling demonstrated by decreased left ventricular internal diameter in diastole (LVIDD) as compared to a control compound. Increased Ki-67+ cells were observed in peri-infarct and distal myocardium of pyrvinium-treated animals. These results need to be further followed-up to determine if therapeutic inhibition of canonical Wnt may avert adverse remodeling after ischemic injury and its impact on myocardial repair and regeneration.
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Sarika
authors.initials: S
authors.lastname: Saraswati
authors.forename: Maria P
authors.initials: MP
authors.lastname: Alfaro
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Thorne
authors.forename: James
authors.initials: J
authors.lastname: Atkinson
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.forename: Pampee P
authors.initials: PP
authors.lastname: Young
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D060466:Axin Protein; D048128:Casein Kinase Ialpha / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011774:Pyrvinium Compounds / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D011774:Pyrvinium Compounds; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C024631:pyrvinium; D048128:Casein Kinase Ialpha