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.

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

“…Our in vivo chemical screen using WNT-974 has identified a tissue that is not detrimentally affected by suppression of Wnt signaling and that may benefit from diminished fibrotic responses induced by Porcn inhibition. Indeed, other classes of small molecules with inhibitory activity for Wnt signaling have similarly shown beneficial responses in heart tissue; albeit, these molecules have not progressed further in clinical development for managing heart disease (42,43). We also reason that other tissues, like the heart (Fig.…”

Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells

“…Cells were then treated with ANG II (10 Ϫ7 M) for 16 h. An additional group of cells was treated with either an inhibitor of the Wnt signaling pathway (pyrvinium pamoate; 10 Ϫ9 M) or an AT1 receptor (candesartan; 10 Ϫ7 M) blocker. The dose of pyrvinium pamoate was based on previous studies showing its effectiveness at nanomolar concentrations in reducing ␤ catenin phosphorylation and proliferation in tumor cells (22,28,38,45). Additionally, it has been shown that pyrivinium pamoate selectively potentiates the casein kinase alpha activity with an EC 50 of 10 nM (45).…”

View from the heart: cardiac fibroblasts in development, scarring and regeneration

“…In general, strategies involving the use of Wnt antagonists throughout myocardial remodelling after infarct exert beneficial effects on myocardial function due to the modulation of fibroblast activity and reduction of scarring (Barandon et al, 2003(Barandon et al, , 2005He et al, 2010;Laeremans et al, 2011;Matsushima et al, 2010;Saraswati et al, 2010). Paradoxically, however, removal of the (Furtado et al, 2014a).…”