Abstract 298: Effects of Long-Term Autophagy Inhibition With Chloroquine on the Development and Progression of Experimental Abdominal Aortic Aneurysms
Bibliographic record
Abstract
Abdominal aortic aneurysms (AAA) are a significant cause of worldwide mortality and morbidity. Although several mechanisms have been put forth, the central determinants of progressive AAA development appear to involve heightened vascular smooth muscle cell (VSMC) apoptosis, with increased degradation of the extracellular matrix, in the setting of chronic inflammation. Recent evidence suggests that autophagy genes are deregulated in human AAA and that autophagy may modulate VSMC fate and plasticity. We sought to determine if long-term autophagy inhibition with chloroquine attenuates AAA progression and mortality in an experimental model of AAA. ApoE-/- mice were implanted with miniosmotic pumps containing either saline (n=15) or angiotensin II (Ang II; 1.44 mg/kg/day) (n=27). Mice from each group were subdivided and administered either the potent autophagy inhibitor chloroquine (50 mg/kg/day, i.p.) or saline for 8 weeks. Hemodynamics, abdominal aortic diameter (by ultrasound) and mortality were monitored. Necroscopy evaluations, histological and immunohistological staining for markers of autophagy, apoptosis and inflammation were conducted. Kaplan-Meier estimates were compared between the four groups over the 8-week follow-up. Ang II infusion was associated with a cumulative mortality of 38%. Long-term chloroquine treatment did not alter Ang II-associated mortality (43%, p>0.05 vs. saline-treated group). When rupture-related AAA mortality was specifically evaluated, no difference between the Ang II groups was observed. Maximal luminal diameter of the abdominal aorta was similar between the Ang II-infused groups (Saline: 1.88±0.13 mm vs. Chloroquine: 1.97± 0.17 mm, p>0.05). Ang II infusion also significantly increased MAP, an effect that was unaffected by chloroquine treatment (Saline: 140±16 mmHg vs. Chloroquine: 135±11 mmHg, p>0.05). Long term chloroquine administration does not alter the development and/or natural history of experimental AAA. These data suggest that a global and non-specific autophagy inhibition strategy is unlikely to represent a target for intervention for AAA. Whether cell- and/or gene-specific targeting of the autophagy machinery improves AAA outcomes remains to be determined.
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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) | 0.002 | 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 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".