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 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.