Canadian Journal of Cardiology
Abstract session by date CCS oral novel approaches to vascular diseases| Volume 28, ISSUE 5, SUPPLEMENT , S282, September 2012

497 BRCA1 Limits AT1-Mediated Redox Signaling, Improves Vascular Reactivity and Reduces Blood Pressure in Spontaneously Hypertensive Rats


      Angiotensin type 1 (AT1) receptor-mediated alterations in redox signalling have been widely implicated in the development and progression of aberrant vascular remodelling and hypertension. Since BRCA1 has been suggested to protect vascular smooth muscle cells from apoptosis and DNA damage in part via regulation of redox signaling and reduction of ROS production, we hypothesized that BRCA1 may serve to restore endothelial function in vivo and in turn reduce blood pressure.


      To evaluate the physiological role of BRCA1 in blood pressure regulation, we employed a transgenic gene delivery approach. Either the BRCA1 adenovirus (AdBRCA1) or the adeno-CMV-null vector (AdNull) was injected into 8-weeks old spontaneously hypertensive rats (SHRs) via their tail veins. An increase in aortic and hepatic expression of BRCA1 was confirmed 6 weeks later in AdBRCA1-treated, but not AdNull-treated, SHRs. Blood pressure, monitored by radiotelemetry, was significantly increased in AdNull-injected SHRs (175±10/131±9 mmHg) relative to SHRs administered AdBRCA1 (156±11/115±9 mmHg, P<0.05). Isolated primary mesenteric arteriole segments, harvested from both groups of SHRs and studied ex vivo in a myograph system, demonstrated similar vasoconstrictive responses to phenylephrine and preserved endothelium-dependent vasorelaxation to acetylcholine. However, mesenteric arteriole rings from AdBRCA1-treated SHRs, relative to those from AdNull-treated SHRs, produced lower maximal vasoconstrictive responses to angiotensin-II (P<0.05). Furthermore, vascular AT1 receptor content, assessed by immunoblotting, was lower in the aortae of SHRs administered AdBRCA1 in comparison to those of AdNull-treated SHRs. These observations were associated with lower NAD(P)H oxidase activation and less superoxide generation in aortas from AdBRCA1-injected SHRs relative to those from AdNull-treated animals.


      We report a novel antihypertensive role for BRCA1-based gene delivery in SHRs. This effect appears to be mediated in part through inhibition of AT1-mediated NAD(P)H oxidase activation and attenuation of angiotensin-II mediated vasoconstriction.