BRCA2欠損内皮細胞：アンジオテンシンII誘発性血管損傷における隠れた触媒

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.