Abstract 2331: BRCA1 Limits Inflammation Induced Apoptosis And Improves Endothelial Function: A Novel Role Of DNA Repair Genes In Vascular Homeostasis
Bibliographic record
Abstract
INTRODUCTION: Endothelial cell apoptosis, in response to inflammatory, ischemic and hypoxic stressors, has been identified as an essential target for therapies aimed at improving graft patency. BRCA1 is a tumor suppressor gene which functions primarily to promote DNA repair, and afford protection against various genotoxic stimuli, including immunosuppressant and chemotherapeutic regimens often employed post-transplantation. We hypothesized that BRCA1 is a novel target to limit inflammation-induced endothelial cell apoptosis and to restore endothelial function. METHODS AND RESULTS: In the first series of studies, we used a gain-of-function approach by adenoviral BRCA1 overexpression in human umbilical vein endothelial cells (HUVECs). Ad-BRCA1-expressing HUVECs exhibited profound protection against TNFα (20 ng/ml)-induced apoptosis, as assessed by flow cytometry, DNA laddering, COMET assay and cleaved procaspase 3 (P < 0.01). This response was mediated by complete prevention of TNFα-induced increases in endothelial ROS production (P < 0.001, vs. Ad-BRCA1). Furthermore, Ad-BRCA1 overexpression prevented TNFα-induced reduction in key indices of endothelial function, namely capillary-like tube formation (P < 0.01) and cell migration (P < 0.01). The protective effects of BRCA1 were not mediated by changes in total or phosphorylated p53 (P = 0.1) but were associated with a significant 6-fold upregulation in eNOS (P < 0.05). A loss-of-function strategy with BRCA1 gene silencing reversed the effects on endothelial apoptosis, ROS production and eNOS phosporylation. CONCLUSIONS: BRCA1 protects endothelial cells against inflammation-induced apoptosis, through a mechanism that involves up-regulation of eNOS and reduced ROS production, and is a novel candidate gene to limit aberrant vascular remodeling. These data also suggest that patients with BRCA1 mutations or cancer syndromes may be at an exaggerated risk of native and transplant atherosclerosis and graft dysfunction, particularly in the setting of DNA damaging immunosuppressants.
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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) | 0.000 | 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".