Abstract 4363268: Scar formation and recovery from myocardial infarction can be modulated by targeting ADAM17 in fibroblasts vs. myofibroblasts
Bibliographic record
Abstract
Background: Myocardial infarction (MI) triggers a complex remodeling process. Disintegrin and metalloproteinase-17 (ADAM17) is a membrane-bound proteinase with a broad range of substrates. Increased ADAM17 in ischemic injury has been reported and linked to adverse outcomes, but its direct role in recovery from MI has not been identified. We aimed to determine the role of ADAM17 in the function of homeostatic (quiescent) fibroblasts (FBs) versus activated myofibroblasts (myoFBs) in scar formation, cardiac remodeling and recovery following MI. Methods and Results: We generated two inducible genetic mouse models with Adam17 knockdown in homeostatic FBs ( Adam17 f/f / Tcf21- Cre Esr1 ; Adam17 FB-KD ) or in myofibroblasts ( Adam17 f/f / Posn Cre ERT ; Adam17 myoFB-KD ), and subjected male and female to MI (by LAD ligation). Loss of ADAM17 in FBs increased left ventricle (LV) rupture due to suppressed collagen cross-linking and impaired scar formation. In contrast, ADAM17 loss in myoFBs limited infarct expansion and LV dilation up to 4 weeks post-MI. Further, ADAM17 loss in myoFBs increased coronary artery density (CD31 immunostaining, 3-D microCT scan), which was found to be due to reduced stiffness of the infarct tissue in these mice (indentation test using Mach-1 Biomomentum mechanical tester). Molecular analyses showed that ADAM17 loss in myoFBs suppresses the epidermal growth factor receptor (EGFR)-Yes-associated protein (YAP) pathway, reducing mechanical stiffness. FBs (passage 1) and myoFBs (activated with TGFβ) were isolated from adult mouse hearts and incubated in normoxia or hypoxia (1% O 2 ) to mimic the in vivo conditions. In vitro co-culture of myoFBs and endothelial cells (ECs) revealed that Adam17 -deficient myoFBs promote EC proliferation and vascular sprouting, consistent with the in vivo observation. Furthermore, pharmacological inhibition of ADAM17 before onset of MI was ineffective, but short-term ADAM17 inhibition after MI (days 1-4, targeting myoFBs) preserved cardiac structure&function up to 4 weeks. Conclusions: Short-term inhibition of ADAM17 after MI (targeting myoFBs) optimizes the compliance of the newly synthesized infarct tissue and promotes vascularization, limits infarct expansion, and prevents long-term adverse LV remodeling, dysfunction, and heart failure.
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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 | 0.000 |
| 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 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".