title: Temporary, Systemic Inhibition of the WNT/β-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct.
abstract: OBJECTIVE
  The WNT/β-catenin pathway is temporarily activated in the heart following myocardial infarction (MI). Despite data from genetic models indicating both positive and negative roles 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.
  
  
  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 vitrostudies showed that WNT inhibition increased proliferation of Sca1+cardiac progenitors, improved survival of cardiomyocytes, and inhibited collagen I synthesis by cardiac myofibroblasts.
  
  
  CONCLUSIONS
  Systemic, temporary pharmacologic inhibition of the WNT pathway using an 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.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Dikshya
authors.initials: D
authors.lastname: Bastakoty
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Sarika
authors.initials: S
authors.lastname: Saraswati
authors.affiliation: Interdisciplinary Graduate Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Piyush
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA.
authors.forename: James
authors.initials: J
authors.lastname: Atkinson
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Feoktistov
authors.affiliation: Genomics Institute of Novartis Research Foundation, San Diego, California, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Genomics Institute of Novartis Research Foundation, San Diego, California, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA; Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Pampee P
authors.initials: PP
authors.lastname: Young
keywords: Myocardial infarct; Regenerative cardiac repair; WNT/β-Catenin Pathway