Abstract 285: Granzymes: Major Players in Vascular Remodelling, Atherosclerosis and Longevity
Bibliographic record
Abstract
Introduction: Granzymes A and B (GrA/GrB) are cytotoxic proteases that are released by immune cells to eliminate target cells. GrB is present in human vessels and its expression corresponds to increased disease severity. In addition to their cytotoxic roles, in conditions of chronic inflammation, GrA and GrB may contribute to the degradation of extracellular matrix (ECM) proteins leading to tissue degeneration. Hypothesis: GrA and GrB levels are elevated in atherosclerotic patients and play a key role in the degradation of ECM and atherosclerosis. Methods: ApoE −/− x GrB −/− double knockout (apoE/GrB-DKO) mice were generated. C57-wt, GrB-KO, apoE-KO or apoE/GrB-DKO mice were fed a high fat diet for 30 weeks, sacrificed, tissues processed and lesion morphology and morphometry assessed. GrA and GrB levels were also measured in human plasma from patients with or without clinically evident atherosclerosis by ELISA. GrA/GrB-mediated ECM proteolytic activity was also assessed. Results: GrB deficiency significantly reduced the development of xanthomatosis, hair loss and atherosclerosis in the apoE-KO mice. GrB deficiency resulted in a marked reduction of elastin degradation in both the skin and blood vessels. GrB was found to co-localize to elastin fibres in atherosclerotic plaques and was capable of binding to, and cleaving elastin in vitro. ECM cleavage assays demonstrated that GrA and GrB cleave other ECM such as fibronectin. Preliminary studies indicate that GrB deficiency increases the lifespan of the apoE-KO mice as the apoE/GrB-DKO mice can survive up to 60 weeks of age on a high fat diet with no external indication of disease, skin degeneration or hair loss. In humans, preliminary evidence indicates that GrA/GrB levels are elevated in atherosclerosis. Smoking also appears to elevate plasma granzyme levels. Conclusions: During chronic inflammation, granzymes accumulate extracellularly and exhibit proteolytic activity towards extracellular matrix proteins that results in vascular remodeling and atherosclerosis with age. Attenuation of GrB resulted not only in a significant reduction of atherosclerosis, but also prolonged the lifespan of apoE-KO mice.
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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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.011 | 0.005 |
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".