Abstract 282: Role of a Disintegrin and Metalloproteinase 15 in Cardiac Hypertrophy and Fibrosis Following Pressure Overload
Bibliographic record
Abstract
Introduction: Disintegrin and metalloproteinases (ADAMs) are membrane-bound cell surface enzymes that are capable of both proteolytic functions (via the metalloproteinase domain) and adhesive functions (via the disintegrin domain), whereby they can influence cell function and extracellular matrix (ECM) remodelling in the heart. ADAM15 is unique among the ADAMs, as it is also capable of degrading ECM proteins. ADAM12 and ADAM17 have been reported to regulate cardiac hypertrophy, but the role of ADAM15 in cardiac hypertrophy is not known. This study investigates the role of ADAM15 in cardiac hypertrophy and fibrosis following pressure overload. Methods & Results: Genetically modified male ADAM15-deficient ( Adam15 -/- ) and wildtype (WT) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC). Cardiac function and structural remodelling were assessed using echocardiography at 2-, and 6-wks post-TAC. Hearts were excised at 2-, or 6-wks post-TAC. Adam15 -/- hearts presented greater hypertrophy and decreased cardiac systolic function at 6wks post-TAC, but no difference at 2wks post-TAC compared to WT-TAC mice. Adam15 -/- hearts also showed exacerbated fibrosis at 6wks post-TAC, but not at 2wks post-TAC, compared to WT. Mechanical strain (i.e. pressure overload) triggers two temporally activated pathways leading to an initial compensatory hypertrophy, which can culminate to decompensation and dilated cardiomyopathy. Consistent with the greater hypertrophy, phosphorylation of ERK1/2, JNK1/2/3, and GSK3β was increased in Adam15 -/- mice. The calcineurin-NFAT pathways can mediate pressure overload-induced hypertrophy, but we found that Adam15-deficiency did not impact this pathway. The mechanism responsible for this function of ADAM15 requires further investigation. Conclusion: This study reports a novel cardioprotective function for ADAM15 in pressure overload, where loss of ADAM15 promotes cardiac fibrosis and decompensated cardiac hypertrophy but does not alter the compensated hypertrophic response.
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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) | 0.000 | 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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".