Document Detail


Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation.
MedLine Citation:
PMID:  16843452     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Karsten Grote; Magdalene Ortmann; Gustavo Salguero; Carola Doerries; Ulf Landmesser; Maren Luchtefeld; Ralf P Brandes; Wilfried Gwinner; Thomas Tschernig; Ernst-Georg Brabant; Andreas Klos; Arnd Schaefer; Helmut Drexler; Bernhard Schieffer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-05-26
Journal Detail:
Title:  Cardiovascular research     Volume:  71     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-31     Completed Date:  2006-10-06     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  596-605     Citation Subset:  IM    
Affiliation:
Department of Cardiology and Angiology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Grote.Karsten@MH-Hannover.DE
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II Type 1 Receptor Blockers / pharmacology
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Animals
Antioxidants / pharmacology
Blood Pressure / drug effects,  physiology*
Cardiomegaly / physiopathology
Cyclic N-Oxides / pharmacology
Endothelium, Vascular / physiopathology
Kidney / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidase / deficiency,  physiology*
Oxidative Stress / drug effects
Reactive Oxygen Species / metabolism
Renin / blood
Renin-Angiotensin System / physiology*
Reverse Transcriptase Polymerase Chain Reaction / methods
Spin Labels
Chemical
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Angiotensin-Converting Enzyme Inhibitors; 0/Antioxidants; 0/Cyclic N-Oxides; 0/Reactive Oxygen Species; 0/Spin Labels; 2226-96-2/tempol; EC 1.6.3.1/NADPH Oxidase; EC 1.6.3.1/neutrophil cytosolic factor 1; EC 3.4.23.15/Renin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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