BRCA1 shields vascular smooth muscle cells from oxidative stress.

BACKGROUND:Excessive production of reactive oxygen species in part via upregulation of DNA damage pathways, is a central mechanism governing pathologic activation of vascular smooth muscle cells (VSMCs). We hypothesized that the breast cancer 1, early onset (BRCA1) gene that is involved in cellular resistance to DNA damage limits production and oxidative stress in VSMCs. METHODS:We evaluated basal and H2O2-stimulated expression of BRCA1 in human aortic smooth muscle cells (HASMCs). In vitro gain-of-function experiments were performed in BRCA1 adenovirus (Ad-BRCA1)-transfected HASMCs. duanyu1670 production and expression of Nox1 and its key regulatory subunit p47phox, key components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, were evaluated. In vivo gain-of-function experiments were performed in spontaneously hypertensive (SHR) rats treated with Ad-BRCA1 (5 × 10(10) IU/rat). Blood pressure, vascular duanyu1670 generation, Nox1, and p47phox expression were measured. RESULTS:BRCA1 was constitutively expressed in murine, rat, and human smooth muscle cells (SMCs). H2O2 significantly reduced BRCA1 expression with a resultant increase in duanyu1670 generation. BRCA1-overexpressing HASMCs were protected against H2O2-induced duanyu1670 generation, in part, via downregulation of the NADPH oxidase subunits Nox1 and p47phox. Ad-BRCA1 treatment in SHR rats was associated with a sustained increase in aortic BRCA1 expression, lower aortic duanyu1670 production, reduced γH2A.X levels, greater RAD51 foci, and decreases in blood pressure. CONCLUSIONS:BRCA1 is a novel and previously unrecognized target that may shield VSMCs from oxidative stress by inhibiting NADPH Nox1-dependent duanyu1670 production. Gene- and/or cell-based approaches that improve BRCA1 bioavailability may represent a new approach in the treatment of diverse vascular diseases associated with an aberrant VSMC phenotype.

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