Abstract 4364679: Endothelial ADAM17 is essential in recovery from myocardial infarction by limiting cell death, promoting vascularization and optimizing infarct formation
Bibliographic record
Abstract
Introduction: Myocardial infarction (MI) is a leading cause of death worldwide, and endothelial cells (ECs) are central to the repair process by coordinating angiogenesis, immune cell recruitment, and endothelial-to-mesenchymal transition (EndMT). ADAM17, a membrane-bound protease elevated in cardiovascular disease, regulates multiple cellular processes through ectodomain shedding of different molecules. However, the causal role of endothelial ADAM17 in post-MI recovery remains poorly defined. Methods: Male and female mice with inducible endothelial-specific ADAM17 knockdown ( Adam17 f/f / Cdhr5 Cre ERT ; Adam17 EC-KD ) and control cohorts ( Adam17 f/f , Cdhr5 Cre ERT , WT) underwent left anterior descending coronary artery ligation to induce experimental MI. Cardiac structure and function were evaluated (echocardiography), histological analyses (Trichrome staining), molecular analyses (immunofluorescent staining (IF), western blotting, and single-nucleus RNA sequencing (snRNA-seq)) at various post-MI time points. Results: Adam17 EC-KD mice exhibited reduced post-MI survival (increased LV rupture), increased left ventricular rupture, and progressive decline in cardiac function with reduced ejection fraction. Adam17 EC-KD mice exhibited increased neutrophil infiltration, NETosis, and cytotoxic T cell accumulation at 1 day post-MI; however, depletion of any of these immune cells further exacerbated the post-MI mortality (due to LV rupture), highlighting their potential protective contribution. Loss of endothelial ADAM17 resulted in decreased coronary density in the infarct myocardium (CD31 IF; 3-D micro-CT imaging), with reduced pVEGFR2 signaling, suggesting impaired angiogenesis. In addition, SnRNA-seq confirmed the suppressed pro-angiogenic pathways, and identified an endothelial cell subpopulation enriched for necroptotic markers, displaying increased ligand-receptor interactions with inflammatory macrophages. Mechanistically, endothelial ADAM17 deficiency enhanced necroptotic cell death via activation of the TNFR1-RIP3K-RIP1K-MLKL axis. Adam17 EC-KD hearts also showed impaired collagen crosslinking and reduced activation of the SMAD pathway (pSMAD2/3), lysyl oxidase, and Fibronectin expression, indicating defective EndMT, supported by reduced EndMT gene signatures in snRNA-seq. Conclusion: Endothelial ADAM17 is essential for effective post-MI cardiac repair by regulating endothelial survival, angiogenesis, immune cell infiltration, and infarct formation.
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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".