  The BReast CAncer type 2 susceptibility protein (BRCA2) responds to DNA
damage by participating in homology-directed repair. BRCA2 deficiency
culminates in defective DNA damage repair (DDR) that when prolonged leads to
the accumulation of DNA damage causing cancer or apoptosis. Oxidative stress
promotes DNA damage and apoptosis and is a common mechanism through which
cardiovascular risk factors lead to endothelial dysfunction and
atherosclerosis. Herein, we show that endothelial BRCA2 plays a protective role
against atherosclerosis under hypercholesterolemic stress. We successfully
generated and characterized endothelial cell (EC)-specific BRCA2 knockout
(BRCA2endo) mice. To study the effect of EC-specific BRCA2-loss in
atherosclerosis, we generated and characterized BRCA2endo mice on
apolipoprotein E null background (ApoE-/-), fed them with high-fat diet (HFD)
and evaluated atherosclerosis. Baseline phenotyping of BRCA2endo mice did not
show any adverse effects in terms of DNA damage and apoptosis as well as
cardiac and metabolic function. However, using HFD-fed apolipoprotein E
knockout (ApoE-/-) background, we demonstrated that EC-specific loss of BRCA2
resulted in aortic plaque deposition and splenomegaly. Comparison of RNA
sequencing data from aortas of EC-specific BRCA2-deficient ApoE-/- and
BRCA2-intact ApoE-/- mice revealed a total of 530 significantly differentially
expressed genes with Protein Folding Response and Lipid Metabolism as the most
affected pathways. This study provides foundational knowledge regarding BRCA2
status and function in the cardiovascular system, and highlights the potential
of BRCA2 as a novel therapeutic target in prevention and treatment of
atherosclerosis. Our data indicate that BRCA2 mutation carriers may be at a
previously unrecognized risk of atherosclerosis in addition to breast and
ovarian cancer.
