Breast Cancer Susceptibility Gene 2 Deficiency Exacerbates Angiotensin‐II‐induced Endothelial Dysfunction and Apoptosis
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 (ED) and cardiovascular diseases (CVDs). ED is an early event in the progression of CVD like hypertension. However, the roles of BRCA1 and BRCA2 in hypertension‐associated ED has not been evaluated. Angiotensin‐II (Ang‐II) treatment is a robust model of endothelial dysfunction and hypertension. We hypothesize that loss of endothelial BRCA2 exacerbate Ang‐II‐induced endothelial dysfunction and apoptosis. Methods We measured baseline and Ang‐II induced expression of BRCA1 and BRCA2 in Human Umbilical Vein Endothelial Cells (HUVECs). BRCA2 was silenced and biomarkers for endothelial function (angiogenic potential, inflammation, and apoptosis) were evaluated following Ang‐II treatment. Results Baseline expression of BRCA1 and BRCA2 in HUVECs were confirmed. We observed a significant up‐regulation of BRCA2 in Ang‐II‐treated HUVECs in comparison to vehicle‐treated control HUVECs. Surprisingly, BRCA1 expression was not affected following Ang‐II treatment of HUVECs. Next, to elucidate the role of BRCA2, we successfully silenced the gene using siBRCA2 in HUVECs and evaluated endothelial function and apoptosis in Ang‐II treated, BRCA2‐silenced and scrambled control HUVECs. We measured the angiogenic potential of Ang‐II treated BRCA2‐silenced HUVECs via matrix gel assay, and observed a significant reduction compared to control HUVECs. Our data also showed a significant upregulation of the endothelial inflammation biomarkers: ICAM, VCAM and E‐selectin in Ang‐II‐treated BRCA2‐silenced HUVECs compared to Ang‐II‐treated control HUVECs. We further observed a significant upregulation of pro‐apoptotic p53 in Ang‐II treated, BRCA2‐silenced HUVECs, which coincided with an observed reduction in survival rate in these HUVECs. Our data on p21, an essential regulator of endothelial cell proliferation, demonstrated a significant upregulation; indicating reduced endothelial proliferation in Ang‐II treated, BRCA2‐silenced HUVECs in comparison to control HUVECs. Conclusion This is the first report investigating the roles of endothelial BRCA1 and BRCA2 after Ang‐II treatment to endothelial cells. We demonstrate a novel role for BRCA2 as a regulator for endothelial function and shows that loss of BRCA2 significantly exacerbates Ang‐II induced inhibition of angiogenic potential, increased inflammation, and apoptosis in endothelial cells. These findings indicate an increased susceptibility of BRCA2 mutation carriers for hypertension‐associated endothelial dysfunction and warrant further translational investigations. Support or Funding Information Funded by Canadian Institutes of Health Research, Canada to KS (FRN # 153216). KS is a recipient of the 2018/19 National New Investigator Award from the Heart and Stroke Foundation of Canada, Canada.
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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".