Loss of BReast CAncer Susceptibility Gene 2 Exacerbates Angiotensin‐II‐induced Endothelial Dysfunction
Bibliographic record
Abstract
Background Germ‐line mutations in the tumour suppressor genes BRCA1 and BRCA2 ( BR east CA ncer susceptibility genes 1 & 2 ) predispose carriers to breast cancer. BRCA1 and BRCA2 help maintain genomic integrity by tracking DNA damage, and evoking DNA damage repair or cell cycle arrest pathways. These pathways play important roles in not only cancer, but also in the development of endothelial dysfunction, an early event in the progression of CVD like hypertension. However, the roles of BRCA1 and BRCA2 in hypertension‐associated endothelial dysfunction has not been evaluated. We hypothesize that loss of endothelial BRCA2 exacerbates Angiotensin‐II (Ang‐II)‐induced endothelial dysfunction. Methods and Results Ang‐II treatment is a robust model of endothelial dysfunction in vitro and hypertension in vivo . We measured baseline and Ang‐II induced expression of BRCA1 and BRCA2 in Human Umbilical Vein Endothelial Cells (HUVECs) and observed a significant up‐regulation of only BRCA2 in Ang‐II‐treated HUVECs. BRCA2 was silenced and biomarkers for endothelial function (inflammation, migration and proliferation) were evaluated following Ang‐II treatment. Our data showed a significant up‐regulation of the endothelial inflammation markers: ICAM‐1, VCAM‐1 and E‐selectin in Ang‐II‐treated BRCA2‐silenced HUVECs compared to Ang‐II‐treated control HUVECs. Next, we evaluated angiogenic potential by evaluating the migratory capacity by scratch assay, which demonstrated reduced migration in Ang‐II‐treated BRCA2‐silenced HUVECs compared to Ang‐II‐treated control HUVECs. At the molecular level, reduced migration was associated with significantly reduced Akt and eNOS activation in Ang‐II‐treated BRCA2‐silenced HUVECs compared to Ang‐II‐treated control HUVECs. Loss of BRCA2 in endothelial cells following Ang‐II treatment inhibited cell proliferation due to significant up‐regulation of p21, an essential regulator of endothelial cell proliferation, in Ang‐II‐treated BRCA2‐silenced HUVECs compared to Ang‐II‐treated control HUVECs. Conclusion We demonstrate a novel role for BRCA2 as a regulator for endothelial function and show that loss of BRCA2 significantly exacerbates Ang‐II induced inhibition of angiogenic, migratory & proliferative potential, and increases inflammation in endothelial cells. These findings indicate an increased susceptibility of BRCA2‐mutation carriers for hypertension‐associated endothelial dysfunction and warrant further translational investigations.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".