Abstract 13767: BRCA1 Reduces Oxidative Stress, Up-Regulates Nitric Oxide Production, and Attenuates Endothelial Cell Apoptosis: A Novel Target for Reduced Endothelial Dysfunction
DNA damage responses are important not only for cancer syndromes but also represent a common pathophysiological basis for diverse diseases characterized by increased cellular and oxidative stress. BRCA1, a tumour suppressor gene implicated in breast and ovarian cancers, exerts a multitude of effects on DNA repair and affords resistance against oxidative stress. We hypothesized that BRCA1 may limit endothelial cell apoptosis and dysfunction, a causal component in the development of atherosclerosis. We found in human umbilical vein endothelial cells that BRCA1-overexpression protected against tumor necrosis factor alpha (TNFα)-, oxidized low-density lipoprotein- and doxorubicin-induced apoptosis, while BRCA1-silencing exaggerated apoptosis. Overexpression and silencing of BRCA1 was associated with significantly reduced and enhanced TNFα-induced reactive oxygen species (ROS) production, respectively. Key indices of endothelial function, including cell migration, tube formation and expression of ICAM-1, VCAM-1 and E-selectin, were modulated in a manner consistent with an effect of BRCA1 to limit endothelial apoptosis and improve endothelial cell function. BRCA1 strongly promoted eNOS, p-eNOS and p-Akt, leading to significantly increased nitric oxide (NO) production from BRCA1-overexpressing endothelial cells. BRCA1 also induced VEGF expression and secretion from endothelial cells. Mice treated with adenoviral BRCA1 before being subjected to hind limb ischemia exhibited improved capillary density and enhanced blood flow recovery. In ApoE-/- mice, BRCA1 treatment limited atherosclerotic lesion formation and inflammation, macrophage infiltration and ROS production without affecting the overall lipid profile. Finally, BRCA1 protein and mRNA expression in human atherosclerotic carotid artery samples were markedly attenuated in the plaque region compared to the adjacent plaque-free area. These findings suggest a novel function for BRCA1 to protect endothelial cells against oxidative stress and to improve endothelial function by inducing VEGF and NO production. Our results provide the first biological clue that individuals carrying BRCA1 mutations may exhibit increased susceptibility to cardiovascular diseases.
- © 2012 by American Heart Association, Inc.