Abstract 10824: A Novel Role of Endothelial Autophagy in the Regulation of Thrombosis <i>in vivo</i>
Bibliographic record
Abstract
Background: Arterial thrombosis of native and graft vessels is the inciting event for acute coronary syndromes, and the cause of significant cardiovascular morbidity and mortality. Endothelial cell (EC) dysfunction is believed to play a central role in the pathobiology of thrombosis. ECs are activated upon atherosclerotic plaque rupture and induce the expression of tissue factor (TF) with resultant atherothrombotic sequelae. The molecular basis of how endothelial TF is unregulated remains unknown. We hypothesize that endothelial autophagy, a process involved in cellular homeostasis and stress responses, plays a causal role in the expression of TF, and via this mechanism modulates thrombosis. Methods: We generated EC-specific ATG7 knockout (EC-ATG7 -/- ) mice using CreLoxP technology. We used small interfering RNA (siRNA) to knockdown and characterize the effect of ATG7 inhibition in HUVECs. We also employed intravital microscopy in FeCl 3 -induced carotid and laser-induced cremaster artery injury to evaluate thrombosis. Results: siRNA-mediated knockdown of ATG7 in HUVEC resulted in decreased TF mRNA and protein expression by over 60% (N=3-5; p<0.05). Mean TF mRNA level in EC-ATG7 -/- mice was 43% lower (p<0.05) compared with WT mice, after FeCl 3 -induced carotid artery injury. Time to carotid artery occlusion was significantly prolonged in EC-ATG7 -/- mice compared with WT mice (15.5±2.0 and 31.0±4.0 min, respectively; N=10/group; p=0.003). The time to maximum platelet fluorescence intensity in EC-ATG7 -/- mice was significantly prolonged relative to that for WT mice (1.0±0.6 and 2.3±1.2 min, respectively; N=33-38 thrombi; p<0.0001). Thrombi size, as determined by platelet fluorescence intensity, were significantly smaller in EC-ATG7 -/- vs. WT mice, (1.8±0.7 and 8.2±2.9, respectively; x10 9 ; p=0.049). Conclusions: Knockdown of ATG7 resulted in reduced TF expression in vitro and in vivo. Compared to WT mice, EC-ATG7 -/- mice exhibited 2-fold greater occlusion times and reduced thrombi formation across all models of thrombosis. Taken together, these findings are evidence that endothelial autophagy regulates thrombosis in a TF-dependent manner, and underscores a novel and previously unrecognized target for antithrombotic drug development.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".