Endothelial Cell-specific Loss of Breast Cancer Susceptibility Gene 2 Exacerbates Atherosclerosis
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.
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