Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction
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Bibliographic record
Abstract
Extracellular matrix (ECM) remodeling is a critical aspect of cardiac remodeling following myocardial infarction. Tissue inhibitors of metalloproteinases (TIMPs) are physiological inhibitors of matrix metalloproteinases (MMPs) that degrade the ECM proteins. TIMP3 is highly expressed in the heart, and is markedly downregulated in patients with ischemic cardiomyopathy. We therefore examined the time- and region-dependent role of TIMP3 in the cardiac response to myocardial infarction (MI). TIMP3(-/-) and wild-type (WT) mice were subjected to MI by ligation of the left anterior descending artery. TIMP3(-/-)-MI mice exhibited a significantly compromised rate of survival compared with WT-MI mice, primarily due to increased left ventricular (LV) rupture, greater infarct expansion, exacerbated LV dilation, and greater systolic and diastolic dysfunction. Second harmonic generation imaging of unfixed and unstained hearts revealed greater collagen disarray and reduced density in the TIMP3(-/-) infarct myocardium compared with the WT group. Gelatinolytic and collagenolytic activities increased in TIMP3(-/-) compared with WT hearts at 1 day post-MI but not at 3 days or 1 wk post-MI. Neutrophil infiltration and inflammatory MMPs were significantly increased in the infarct and peri-infarct regions of TIMP3(-/-)-MI hearts. Treatment of TIMP3(-/-) mice with a broad-spectrum MMP inhibitor (PD-166793) for 2 days before and 2 days after MI markedly improved post-MI infarct expansion, LV rupture incident, LV dilation, and systolic dysfunction in these mice up to 1 wk post-MI. Our data demonstrate that the initial rise in proteolytic activities early post-MI is a triggering factor for subsequent LV adverse remodeling, LV rupture, and dilated cardiomyopathy. Hence, timing of treatments to improve cardiac response to MI may be critical in producing favorable outcome.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| 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 it