Abstract 4219: BRCA1 is a Novel Regulator of Endothelial Function and Limits Atherosclerosis
DNA damage represents a common mechanism through which various chronic diseases, such as cancer and atherosclerosis develop. BRCA1, a well known tumour suppressor gene, implicated in breast and ovarian cancer syndromes, exerts a multitude of effects on DNA repair, and affords resistance against cellular stress responses. We hypothesized that BRCA1 may function to limit endothelial dysfunction, a causal factor in the development of atherosclerosis. We demonstrate that overexpression of BRCA1 protects, whereas gene silencing of BRCA1 exaggerates inflammation- and doxorubicin-induced apoptosis of human umbilical vein endothelial cells (P<0.01). Key indices of endothelial cell function, such as the ability of endothelial cells to migrate, form capillary-like tubes and express surface markers of endothelial injury (ICAM-1, VCAM-1 and E-selectin) are modulated in manner consistent with an effect of BRCA1 to limit endothelial apoptosis and improve endothelial cell function (p<0.001). Furthermore, in vivo adenoviral BRCA1 treatment of mice subjected to hindlimb ischemia improves capillary density and restores recovery of blood flow. From a mechanistic perspective, BRCA1 strongly upregulated eNOS, p-eNOS, p-Akt and VEGF expression, and promoted cell growth arrest under G1/G0 phase through a p21-dependent process. We generated endothelial cell specific BRCA1 heterozygous deficient mice which were born with disrupted Mendelian distribution and exhibited increased susceptibility to apoptosis and increased embroyonic mortality. Importantly, BRCA1 treatment limited atherosclerotic lesion formation and inflammation in a well established model of atherosclerosis, the ApoE−/− mouse. Lastly, in human atherosclerosis specimens BRCA1 protein and mRNA expression were markedly attenuated in plaque compared to plaque adjacent areas. These data highlight a previously unrecognized role of BRCA1 as a gatekeeper of endothelial cell function, and a potentially novel treatment approach to limit atherosclerosis. Furthermore, these data provide the first biological clue that individuals who carry BRCA1 mutations may exhibit increased susceptibility to cardiovascular disease.