Critical role for p47phox in renin–angiotensin system activation and blood pressure regulation

doi:10.1016/j.cardiores.2006.05.020

Critical role for p47^phox in renin–angiotensin system activation and blood pressure regulation

^aDepartment of Cardiology and Angiology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
^bInstitut of Cardiovascular Physiology, Clinical Center of the J.W. Goethe-University, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany
^cDepartment of Nephrology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
^dDepartment of Anatomy, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
^eDepartment of Endocrinology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
^fDepartment of Medical Microbiology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany

* Corresponding author. Tel.: +49 511 532 9584; fax: +49 511 532 3263. Email address: Grote.Karsten{at}MH-Hannover.DE

Received November 30, 2005.
Revision received May 4, 2006.
Accepted May 23, 2006.

Abstract

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 C57BL/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 post partum. 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.

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