Lack of Tissue Inhibitor of Metalloproteinases 2 Leads to Exacerbated Left Ventricular Dysfunction and Adverse Extracellular Matrix Remodeling in Response to Biomechanical Stress
Bibliographic record
Abstract
BACKGROUND: Remodeling of the extracellular matrix (ECM) is a key aspect of myocardial response to biomechanical stress and heart failure. Tissue inhibitors of metalloproteinases (TIMPs) regulate the ECM turnover through negative regulation of matrix metalloproteinases (MMPs), which degrade the ECM structural proteins. Tissue inhibitor of metalloproteinases 2 is unique among TIMPs in activating pro-MMP2 in addition to inhibiting a number of MMPs. Given this dual role of TIMP2, we investigated whether TIMP2 serves a critical role in heart disease. METHODS AND RESULTS: Pressure overload by transverse aortic constriction (TAC) in 8-week-old male mice resulted in greater left ventricular hypertrophy, fibrosis, dilation, and dysfunction in TIMP2-deficient (TIMP2(-/-)) compared with wild-type mice at 2 weeks and 5 weeks post-TAC. Despite lack of MMP2 activation, total collagenase activity and specific membrane type MMP activity were greater in TIMP2(-/-)-TAC hearts. Loss of TIMP2 resulted in a marked reduction of integrin β1D levels and compromised focal adhesion kinase phosphorylation, resulting in impaired adhesion of cardiomyocytes to ECM proteins, laminin, and fibronectin. Nonuniform ECM remodeling in TIMP2(-/-)-TAC hearts revealed degraded network structure as well as excess fibrillar deposition. Greater fibrosis in TIMP2(-/-)-TAC compared with wild-type TAC hearts was due to higher levels of SPARC (secreted protein acidic and rich in cysteine) and posttranslational stabilization of collagen fibers rather than increased collagen synthesis. Inhibition of MMPs including membrane type MMP significantly reduced left ventricular dilation and dysfunction, hypertrophy, and fibrosis in TIMP2(-/-)-TAC mice. CONCLUSIONS: Lack of TIMP2 leads to exacerbated cardiac dysfunction and remodeling after pressure overload because of excess activity of membrane type MMP and loss of integrin β1D, leading to nonuniform ECM remodeling and impaired myocyte-ECM interaction.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".