Journal
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Volume 147, Issue 6, Pages 1946-U298Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jtcvs.2013.09.060
Keywords
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Funding
- Heart and Stroke Foundation of Canada
- Canadian Institutes of Health Research
- Sanofi-Aventis Canada Inc
- Roche Canada
- Abbott Canada
- AstraZeneca Canada
- Canada Research Chair in Atherosclerosis at the University of Toronto
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Background: Excessive production of reactive oxygen species (ROS), 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 ROS 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. ROS production and expression of Nox1 and its key regulatory subunit p47phox, key components of the ROS-generating 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 x 10(10) IU/rat). Blood pressure, vascular ROS 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 ROS generation. BRCA1-overexpressing HASMCs were protected against H2O2-induced ROS generation, in part, via downregulation of the ROS-producing NADPH oxidase subunits Nox1 and p47phox. Ad-BRCA1 treatment in SHR rats was associated with a sustained increase in aortic BRCA1 expression, lower aortic ROS production, reduced gamma H2A.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 ROS 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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