Beyond cancer: breast cancer gene 2 emerges as a new player in atherosclerosis

Atherosclerosis is a chronic immunoinflammatory disease driven by endothelial dysfunction, oxidative stress, and DNA damage. Although breast cancer gene 2 (BRCA2) is a key regulator of homologous recombination-mediated DNA damage repair, its role in vascular biology remains unclear. We hypothesized that endothelial BRCA2 protects against atherogenesis under stress conditions. Endothelial-specific BRCA2 knockdown mice (BRCA2^EC-KO) were generated using a vascular endothelial (VE)-cadherin-Cre/loxP system. Baseline phenotyping included assessment of DNA damage, apoptosis, cardiac function, and metabolic parameters. Subsequently, BRCA2^EC-KO mice were generated on an ApoE^-/- background (BRCA2^EC-KO;ApoE^-/-) and characterized. Atherosclerosis was then evaluated in the aorta following high-fat diet (HFD), with quantification of plaque burden, necrotic core area, collagen content, and macrophage infiltration. Plasma lipid levels were measured. Mechanistic studies included RNA sequencing of aortic tissue and in vitro experiments in BRCA2-silenced cultured endothelial cells treated with oxidized LDL (oxLDL), assessing unfolded protein response (UPR) and heme oxygenase-1 (HO-1) expression. Loss of endothelial BRCA2 had no effect on baseline viability, DNA damage, apoptosis, cardiac function, or metabolism in BRCA2^EC-KO mice. However, BRCA2^EC-KO;ApoE^-/- mice exhibited significantly increased plaque burden, necrotic core formation, collagen deposition, and vascular inflammation after HFD, without changes in plasma lipids. These mice also developed splenomegaly with reduced HO-1 expression. Transcriptomic analysis revealed enrichment of pathways related to UPR, oxidative stress, and cholesterol metabolism. In vitro, BRCA2 deficiency exacerbated oxLDL-induced UPR and attenuated HO-1 expression. These findings identify endothelial BRCA2 as a critical regulator of vascular stress responses and atheroprotection, revealing a previously unrecognized link between DNA repair pathways and cardiovascular disease.NEW & NOTEWORTHY This study uncovers a novel role for endothelial BRCA2 in limiting atherosclerosis. Endothelial cell-specific loss of BRCA2 is dispensable at baseline, but under high-fat diet stress, it significantly worsens atherosclerosis and causes splenomegaly. BRCA2 also regulates pathways beyond DNA repair in endothelial cells. These findings identify a new potential therapeutic target for atherosclerosis and suggest that individuals with BRCA2 mutations may have increased cardiovascular risk, expanding the known impact of BRCA2 beyond cancer susceptibility.