BRCA1 adenovirus

BRCA1 is a tumor suppressor gene implicated in breast and ovarian cancer that has multiple effects on DNA repair and protects against cellular stress responses. Here, researchers show that BRCA1 is expressed primarily in endothelial cells. BRCA1 overexpression protects against endothelial apoptosis, whereas BRCA1 silencing exacerbates inflammation and doxorubicin-induced endothelial apoptosis. Key markers of endothelial function were modulated in a manner consistent with the effects of BRCA1 limiting endothelial apoptosis and improving endothelial function. BRCA1 overexpression strongly attenuated reactive oxygen species production and upregulated the expression of endothelial nitric oxide synthase, phosphorylated endothelial nitric oxide synthase, phosphorylated Akt, and vascular endothelial growth factor-a. BRCA1 overexpression also improved capillary density and promoted blood flow restoration in mice with hindlimb ischemia. BRCA1-overexpressing ApoE^−/− mice had significantly reduced aortic plaque lesions, reduced macrophage infiltration, and reduced reactive oxygen species production on a Western diet. Lung sections and aortic segments of EC-BRCA1^−/− mice exhibited increased inflammation-associated apoptosis and impaired endothelial function, respectively. BRCA1 expression was attenuated in plaque areas of human atherosclerotic carotid artery samples compared with adjacent plaque-free areas.

To assess the potential translational significance of the improved endothelial function in vivo, the researchers examined the extent of neovascularization that occurred after induction of hindlimb ischemia in BALB/c mice. BRCA1 overexpression was confirmed by immunoblotting of tissue lysates isolated from adductor muscles 8 days after surgery (Figure 1A). As early as 8 days after surgery, perfusion in the ischemic limb of mice treated with adenovirus BRCA1 (ad-BRCA1) was significantly increased compared with that of mice treated with ad-null (Figure 1B and C). Perfusion was consistently and significantly increased in the ischemic limb of ad-BRCA1-treated mice (Figure 1B and C). The enhanced restoration of blood flow in mice treated with ad-BRCA1 was associated with a higher capillary density 28 days after ischemia induction compared with ad-null-treated mice (Figure 1D). These data suggest that BRCA1 has an important angiogenic role in vivo.

Figure 1. BRCA1 improves recovery of ischemic hind limb. (Singh K K, et al., 2013)