Published online before print March 22, 2004, doi: 10.1161/01.CIR.0000124223.00113.A4
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(Circulation. 2004;109:1795-1801.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension
From the Institut für Kardiovaskuläre Physiologie (O.J., J.G.S., R.B., R.P.B.) and Medizinische Klinik IV, Funktionsbereich Nephrologie (H.G.), Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany, and the Division of Hypertension, University of Lausanne Medical School, Lausanne, Switzerland (T.P.).
Correspondence to Ralf P. Brandes, MD, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail r.brandes{at}em.uni-frankfurt.de
Received June 16, 2003; de novo received November 6, 2003; accepted January 5, 2004.
Background— Isoforms of the NADPH oxidase contribute to vascular superoxide anion ( · O2–) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O2– to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction.
Methods and Results— Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox–/–) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox–/– mice (158±2 versus 149±2 mm Hg; P<0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox–/– mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox–/– mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox–/– mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice.
Conclusions— These data indicate that the formation of O2– by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.
Key Words: stress, oxidative • angiotensin • endothelium • hypertension
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