Abstract 18248: Reduced β-catenin Expression in Mouse Cardiomyocytes Increases Matrix Metalloproteinase Activation and Apoptosis, Producing Greater Post-Infarction Ventricular Dysfunction
Introduction: The loss of beating cardiomyocytes after myocardial infarction (MI) is followed by detrimental remodelling involving activation of matrix metalloproteinases (MMPs), which can lead to heart failure. β-catenin, a member of the cadherin family, is found at cell-cell junctions and can increase cell survival and promote tissue repair via canonical Wnt signaling. However, its role in the heart has not been characterized. We sought to determine whether β-catenin is important in cardiac remodelling after MI.
Hypothesis: β-catenin signaling in cardiomyocytes mediates cell death and matrix remodelling and contributes to post-infarction ventricular dysfunction.
Methods/Results: The role of β-catenin in cardiomyocytes was evaluated with transgenic mice harboring a floxed mutation for β-catenin driven by a muscle creatine kinase-Cre promoter. Mutant and wild-type (WT) mice were subjected to coronary artery ligation to induce MI, and cardiac function was evaluated by echocardiography. The β-catenin null mice exhibited a 16% decrease in ejection fraction compared to WT controls (69.2±0.9 vs. 59.6±1.0, p<0.05, n=7). Histology revealed greater cardiac thinning and dilatation in the null mice. Histological analysis demonstrated increased β-catenin protein expression in the nuclei of WT myocardium following ligation. TUNEL staining revealed 50% greater apoptosis in the border region of the infarcted myocardium of the null mice (p<0.05). Both WT and null mice had a 4-fold increase in the protein level of the apoptotic markers caspase3 and cleaved parp in the infarct scar compared to the remote region (p<0.05, n=4), which was similar between groups. Gel zymography (to assess MMP2 activity) demonstrated a 60% increase in MMP2 activation within the infarct region (p<0.05, n=4), and Western blot showed a 75% decrease in tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels within the remote region of the null mice (p<0.05, n=4).
Conclusion: The exaggerated ventricular dysfunction in the null mice following injury was due to the depletion of β-catenin in cardiomyocytes. Our data suggest that β-catenin is necessary for the modulation of MMP2 and cell apoptosis to prevent detrimental remodelling and heart failure following MI.
- © 2013 by American Heart Association, Inc.