title: Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation.
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 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Cardiology and Angiology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Grote.Karsten@MH-Hannover.DE
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.forename: Magdalene
authors.initials: M
authors.lastname: Ortmann
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salguero
authors.forename: Carola
authors.initials: C
authors.lastname: Doerries
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.forename: Maren
authors.initials: M
authors.lastname: Luchtefeld
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gwinner
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.forename: Ernst-Georg
authors.initials: EG
authors.lastname: Brabant
authors.forename: Andreas
authors.initials: A
authors.lastname: Klos
authors.forename: Arnd
authors.initials: A
authors.lastname: Schaefer
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D006332:Cardiomegaly / Q000503:physiopathology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013113:Spin Labels
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D012083:Renin; C001803:tempol