Abstract 12721: Brca1 Protects Vascular Smooth Muscle Cells from Oxidative Stress and Reduces Blood Pressure
Background: Redox signaling is gaining ground as a key contributor to the pathogenesis and progression of hypertension. Work in animal models suggest a causal relationship between oxidative stress and the manifestation of hypertension while experimental and clinical evidence implicate excess bioavailability of reactive oxygen species (ROS) in the molecular foundation of elevated blood pressure. The tumor suppressor BRCA1 critically modulates cardiomyocyte and endothelial cell physiology and health. We hypothesized that BRCA1 may reduce blood pressure by attenuating aberrant redox signaling and ROS production in vascular smooth muscle cells (VSMCs).
Methods: In vitro studies were performed on human aortic SMCs (HASMCs) and aortic SMCs from spontaneously hypertensive rats (SHRs). In vivo studies were conducted with 8-week old SHRs and normotensive Wistar-Kyoto rats (WKYs). Gain-of-function was achieved with a custom-designed BRCA1 adenovirus (AdBRCA1); AdNull-treated groups served as controls.
Results: In HASMCs, hydrogen peroxide (H2O2; 100 μM, 24 h) markedly suppressed BRCA1 transcript and protein levels, and increased ROS production and NAD(P)H oxidase activation. These H2O2-elicited effects were absent in AdBRCA1-treated HASMCs. Aortic SMCs from SHRs vs. WKYs revealed significantly lower BRCA1 transcript and protein levels; and appreciably greater basal NAD(P)H oxidase activation and ROS generation, both of which were attenuated in AdBRCA1-treated aortic SMCs. Levels of the NAD(P)H oxidase subunits P47phoxo and NOX1 were significantly enhanced in VSMCs from SHRs vs. WKYs but dampened in corresponding AdBRCA1-treated VSMSCs. Four days after treatment, AdBRCA1-treated SHRs demonstrated a significant 8-15 mmHg lower blood pressure compared to AdNull-treated SHRs. This difference persisted for the next 24 days. NAD(P)H oxidase activation and superoxide production were markedly lower in aortas from AdBRCA1- vs. AdNull-treated SHRs. Elevations in NOX1 and p47phoxo were also less evident in AdBRCA1- vs. AdNull-injected SHRs.
Conclusion: We report a novel antihypertensive role for BRCA1-based gene delivery in SHRs that appears to be mediated in part through attenuation of NAD(P)H oxidase activation and ROS production in VSMCs.
- © 2013 by American Heart Association, Inc.