Abstract 11078: Granzyme B Deficiency Protects Against Angiotensin II-induced Cardiac Fibrosis via a Perforin-independent Mechanism
Bibliographic record
Abstract
Introduction: Granzyme B (GzmB) is a serine protease involved in immune cell-mediated apoptosis that is enabled through a mechanism involving the pore-forming protein, perforin that facilitates internalization. However, recent evidence suggests that GzmB contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. Hypothesis: GzmB contributes to cardiac fibrosis through a perforin-independent pathway involving extracellular proteolysis. Methods: Using a murine model of Angiotensin II (Ang II)-induced cardiac fibrosis, wild-type, GzmB deficient and Perforin deficient mice were treated with Ang II for 4 weeks, and were examined for the presence of cardiac fibrosis. Echocardiography was performed in these mice to examine the cardiac function. The level of Inflammation and inflammatory cells infiltration were examined by immunohistochemistry and RT-PCR analysis. The in vitro endothelial barrier function was measured by electric cell-substrate impedance sensing. Results: GzmB was highly up-regulated in both murine and human cardiac fibrosis. Genetic deficiency of GzmB markedly reduced Ang II-induced cardiac dysfunction, hypertrophy and fibrosis, independently of perforin. GzmB deficiency also decreases microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro studies identified VE-cadherin as a GzmB substrate. VE-cadherin is a key endothelial cell-cell junction protein. GzmB-mediated VE-cadherin cleavage resulted in increased endothelial permeability, and increased transcellular conductance. These results were also observed in vivo. Conclusions: GzmB contributes to the onset and progression of cardiac fibrosis through a perforin-independent process involving the cleavage of VE-cadherin.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".