Bastakoty, Dikshya , Saraswati, Sarika , Atkinson, James , Feoktistov, Igor, Liu, Jun, Harris, Jennifer and Young, Pampee (2016) Temporary, Systemic Inhibition of the WNT/β- Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct. Cell, Stem cells and Regenerative Medicine, 2 (2). pp. 1-13. ISSN 2472-6990

Abstract

Aims: The Wnt/β-catenin pathway is temporarily activated in the heart following myocardial infarction. Despite data from genetic models
indicating both positive and negative role for the Wnt pathway depending on the model used, the effect of therapeutic inhibition of Wnt pathway
on post-injury outcome and the cellular mediators involved are not completely understood. Using a newly available, small molecule, GNF-6231,
which averts Wnt pathway activation by blocking secretion of all Wnt ligands, we sought to investigate whether therapeutic inhibition of the
Wnt pathway temporarily after infarct can mitigate post injury cardiac dysfunction and fibrosis and the cellular mechanisms responsible for
the effects.
Methods and Results: Pharmacologic inhibition of the Wnt pathway by post-MI intravenous injection of GNF-6231 in C57Bl/6 mice
significantly reduced the decline in cardiac function (Fractional Shortening at day 30: 38.71 ± 4.13% in GNF-6231 treated vs. 34.89 ± 4.86% in
vehicle- treated), prevented adverse cardiac remodeling, and reduced infarct size (9.07 ± 3.98% vs. 17.18 ± 4.97%). Wnt inhibition augmented
proliferation of interstitial cells, particularly in the distal myocardium, inhibited apoptosis of cardiomyocytes, and reduced myofibroblast
proliferation in the peri-infarct region. In vitro studies showed that Wnt inhibition increased
proliferation of Sca1+ cardiac progenitors, improved survival of cardiomyocytes, and inhibited collagen I synthesis by cardiac myofibroblasts.
Conclusion: Systemic, temporary pharmacologic inhibition of the Wnt pathway using orally bioavailable drug immediately following MI
resulted in improved function, reduced adverse remodeling and reduced infarct size in mice. Therapeutic Wnt inhibition affected multiple
aspects of infarct repair: it promoted proliferation of cardiac progenitors and other interstitial cells, inhibited myofibroblast proliferation,
improved cardiomyocyte survival, and reduced collagen I gene expression by myofibroblasts. Our data point to a promising role for Wnt
inhibitory therapeutics as a new class of drugs to drive post-MI repair and prevent heart failure.

Item Type:	Article
Keywords:	WNT, Cardiac repair, myocardial infacrt
Date Deposited:	15 Sep 2016 00:45
Last Modified:	15 Sep 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28412