DOI: 10.1097/hjh.0000000000004407 ISSN: 0263-6352
BRCA2-deficient endothelium: a hidden catalyst in angiotensin II-induced vascular injury
Aman Singh, Shuhan Bu, Alexander V. Perron, Kriti S. Bhatt, Inderbir S. Sandhu, Jefferson C. Frisbee, Krishna K. Singh
Background:
Mutations in the breast cancer susceptibility gene 2 (
BRCA2
) are well known to increase the risk of breast and ovarian cancers. Emerging evidence indicates that
BRCA2
mutation carriers exhibit increased vascular disorder and may develop endothelial dysfunction, a key mechanism underlying hypertension. Angiotensin II (Ang II), a central effector of the renin–angiotensin system, is a key regulator of blood pressure and a major driver of hypertension, promoting endothelial injury through oxidative stress, inflammation, and impaired nitric oxide (NO) bioavailability. However, the role of endothelial BRCA2 in Ang II-induced endothelial dysfunction remains unknown.
Methods:
BRCA2
was silenced in cultured endothelial cells and following Ang II treatment, ROS generation, DNA damage, apoptosis, inflammation, NO production, migration, angiogenic capacity, Ang II receptors and related signaling pathways were assessed.
Results:
BRCA2
deficiency exacerbated Ang II-induced increases in ROS, DNA damage, and apoptosis, along with impaired functional capacity, including reduced migration and angiogenesis. NO production was suppressed, accompanied by increased micronuclei formation and enhanced c-Jun N-terminal kinase (JNK) activation. In addition, both
BRCA2
loss and Ang II treatment upregulated the Ang II receptor AT1R. Pharmacological inhibition of AT1R attenuated Ang II-induced increases in DNA damage and apoptosis in
BRCA2
-deficient endothelial cells.
Conclusion:
These findings provide the first pharmacogenomic evidence that
BRCA2
deficiency sensitizes endothelial cells to Ang II-induced dysfunction, suggesting that
BRCA2
mutation carriers may be at increased risk for hypertension-associated cardiovascular complications.