TIMP2 Deficiency Accelerates Adverse Post–Myocardial Infarction Remodeling Because of Enhanced MT1-MMP Activity Despite Lack of MMP2 Activation
Bibliographic record
Abstract
RATIONALE: Myocardial infarction (MI) results in remodeling of the myocardium and the extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) are critical regulators of ECM integrity via inhibiting matrix metalloproteinases (MMPs). TIMP2 is highly expressed in the heart and is the only TIMP that, in addition to inhibiting MMPs, is required for cell surface activation of pro-MMP2. Hence, it is difficult to predict the function of TIMP2 as protective (MMP-inhibiting) or harmful (MMP-activating) in heart disease. OBJECTIVE: We examined the role of TIMP2 in the cardiac response to MI. METHODS AND RESULTS: MI was induced in 11- to 12-week-old male TIMP2(-/-) and age-matched wild-type mice. Cardiac function was monitored by echocardiography at 1 and 4 weeks post-MI. ECM fibrillar structure was visualized using second harmonic generation and multiphoton imaging of unfixed/unstained hearts. Molecular analyses were performed at 3 days and 1 week post-MI on flash-frozen infarct, periinfarct, and noninfarct tissue. Membrane type 1 (MT1)-MMP levels and activity were measured in membrane protein fractions. TIMP2(-/-)-MI mice exhibited a 25% greater infarct expansion, markedly exacerbated left ventricular dilation (by 12%) and dysfunction (by 30%), and more severe inflammation compared to wild-type MI mice. Adverse ECM remodeling was detected by reduced density and enhanced disarray of fibrillar collagen in TIMP2(-/-)-MI compared to wild-type MI hearts. TIMP2 deficiency completely abrogated MMP2 activation but markedly increased collagenase activity, particularly MT1-MMP activity post-MI. CONCLUSIONS: The MMP-inhibitory function of TIMP2 is a key determinant of post-MI myocardial remodeling primarily because of its inhibitory action on MT1-MMP. TIMP2 replenishment in diseased myocardium could provide a potential therapy in reducing or preventing disease progression.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".