Abstract 18248: Reduced β-catenin Expression in Mouse Cardiomyocytes Increases Matrix Metalloproteinase Activation and Apoptosis, Producing Greater Post-Infarction Ventricular Dysfunction
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".