Copyright © 2006, European Society of Cardiology
Critical role for p47phox 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
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 p47phox is critically involved in agonist-induced NAD(P)H oxidase activation. Here, we investigated the role of p47phox in blood pressure control, endothelium-dependent relaxation, cardiac hypertrophy, RAS activation, and renal oxidative stress under resting conditions.
Methods and results Mice deficient in p47phox (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 p47phox – / – mice was associated with an impaired endothelium-dependent relaxation (P<0.005 vs. wild-type, n=11). At the age of 12 weeks p47phox – / – 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 p47phox – / – mice, whereas ACE and angiotensin II type I receptor inhibition normalized blood pressure.
Conclusion Deficiency of the NAD(P)H oxidase subunit p47phox leads to RAS activation, which subsequently contributes to blood pressure increase in a ROS-independent manner.
KEYWORDS NAD(P)H oxidase; p47phox; Reactive oxygen species; Blood pressure; Renin–angiotensin system
1 These authors contributed equally to this work.
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