Critical role for p47phax in renin-angiotensin system activation and blood pressure regulation

Objective: Renin-angiotensin system (RAS) activation leads to increased production of NAD(P)H oxidase-derived reactive oxygen species (ROS), and both have been implicated in the initiation and progression of arterial hypertension, atherosclerosis, and cardiac hypertrophy. The cytosolic subunit p47(phox) is critically involved in agonist-induced NAD(P)H oxidase activation. Here, we investigated the role of p47(phox) in blood pressure control, endothelium-dependent relaxation, cardiac hypertrophy, RAS activation, and renal oxidative stress under resting conditions. Methods and results: Mice deficient in p47(phox) (on C57BL/6 background) developed significantly higher systolic blood pressure levels compared to C5713L/6 wild-type animals (136.0 +/- 3.0 mmHg vs. 112.2 +/- 2.6, P < 0.01, n=16) as measured by the tail cuff method from week 6 up to week 12 postpartum. The increase in blood pressure in p47(phox-/-) mice was associated with an impaired endothelium-dependent relaxation (P < 0.005 vs. wild-type, n=11). At the age of 12 weeks p47(phox-/-) mice showed increased plasma renin activity as analyzed by radioimmunoassay (14.5 +/- 1.8 ng/mL/h vs. 9.6 +/- 1.7 ng/mL/h, P < 0.05, n=10) and enhanced angiotensin converting enzyme (ACE) activity in the kidney and aorta as measured by Hip-His-Leu cleavage (7.6 +/- 0.8 vs. 4.8 +/- 0.9 nmol/L His-Leu/mg protein, P < 0.05, n=5) compared to wild-type mice. No differences in oxygen radical formation was determined in kidney samples by lucigenin- and luminol-enhanced chemiluminescence or by electron spin resonance spectroscopy. Consistently, treatment with the radical scavenger tempol did not lower blood pressure in p47(phox-/-) mice, whereas ACE and angiotensin II type I receptor inhibition normalized blood pressure. Conclusion: Deficiency of the NAD(P)H oxidase subunit p47(phox) leads to RAS activation, which subsequently contributes to blood pressure increase in a ROS-independent manner. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.