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(Hypertension. 2002;40:511.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Role of p47^phox in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II

Ulf Landmesser; Hua Cai; Sergey Dikalov; Louise McCann; Jinah Hwang; Hanjoong Jo; Steven M. Holland; David G. Harrison

From the Division of Cardiology, Emory University School of Medicine and Atlanta Veterans Administration Hospital (U.L., H.C., S.D., L.M., J.H., H.J., D.G.H.), Atlanta, Ga; and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health (S.M.H.), Bethesda, Md.

Correspondence to David G. Harrison, MD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Drive, 319 WMB, Atlanta, GA 30322. E-mail dharr02{at}emory.edu

Hypertension caused by angiotensin II is dependent on vascular superoxide (O₂·-) production. The nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase is a major source of vascular O₂·- and is activated by angiotensin II in vitro. However, its role in angiotensin II-induced hypertension in vivo is less clear. In the present studies, we used mice deficient in p47^phox, a cytosolic subunit of the NADPH oxidase, to study the role of this enzyme system in vivo. In vivo, angiotensin II infusion (0.7 mg/kg per day for 7 days) increased systolic blood pressure from 105±2 to 151±6 mm Hg and increased vascular O₂·- formation 2- to 3-fold in wild-type (WT) mice. In contrast, in p47^phox-/- mice the hypertensive response to angiotensin II infusion (122±4 mm Hg; P<0.05) was markedly blunted, and there was no increase of vascular O₂·- production. In situ staining for O₂·- using dihydroethidium revealed a marked increase of O₂·-production in both endothelial and vascular smooth muscle cells of angiotensin II-treated WT mice, but not in those of p47^phox-/- mice. To directly examine the role of the NAD(P)H oxidase in endothelial production of O₂·-, endothelial cells from WT and p47^phox-/- mice were cultured. Western blotting confirmed the absence of p47^phox in p47^phox-/- mice. Angiotensin II increased O₂·- production in endothelial cells from WT mice, but not in those from p47^phox-/- mice, as determined by electron spin resonance spectroscopy. These results suggest a pivotal role of the NAD(P)H oxidase and its subunit p47^phox in the vascular oxidant stress and the blood pressure response to angiotensin II in vivo.

Key Words: oxidative stress • endothelium • angiotensin II • hypertension, experimental

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				J. Q. Liu and R. J. Folz Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L111 - L118. [Abstract] [Full Text] [PDF]

				K K Griendling Novel NAD(P)H oxidases in the cardiovascular system Heart, May 1, 2004; 90(5): 491 - 493. [Full Text] [PDF]

				M. J. Ryan, S. P. Didion, S. Mathur, F. M. Faraci, and C. D. Sigmund Angiotensin II-Induced Vascular Dysfunction Is Mediated by the AT1A Receptor in Mice Hypertension, May 1, 2004; 43(5): 1074 - 1079. [Abstract] [Full Text] [PDF]

				J.-M. Li, S. Wheatcroft, L. M. Fan, M. T. Kearney, and A. M. Shah Opposing Roles of p47phox in Basal Versus Angiotensin II-Stimulated Alterations in Vascular O2- Production, Vascular Tone, and Mitogen-Activated Protein Kinase Activation Circulation, March 16, 2004; 109(10): 1307 - 1313. [Abstract] [Full Text] [PDF]

				E. Werner GTPases and reactive oxygen species: switches for killing and signaling J. Cell Sci., January 15, 2004; 117(2): 143 - 153. [Abstract] [Full Text] [PDF]

				J. S. McNally, M. E. Davis, D. P. Giddens, A. Saha, J. Hwang, S. Dikalov, H. Jo, and D. G. Harrison Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2290 - H2297. [Abstract] [Full Text] [PDF]

				Y. Taniyama and K. K. Griendling Reactive Oxygen Species in the Vasculature: Molecular and Cellular Mechanisms Hypertension, December 1, 2003; 42(6): 1075 - 1081. [Abstract] [Full Text] [PDF]

				J. Hwang, A. Saha, Y. C. Boo, G. P. Sorescu, J. S. McNally, S. M. Holland, S. Dikalov, D. P. Giddens, K. K. Griendling, D. G. Harrison, et al. Oscillatory Shear Stress Stimulates Endothelial Production of O2- from p47phox-dependent NAD(P)H Oxidases, Leading to Monocyte Adhesion J. Biol. Chem., November 21, 2003; 278(47): 47291 - 47298. [Abstract] [Full Text] [PDF]

				E. Ritz and V. Haxsen Angiotensin II and Oxidative Stress: An Unholy Alliance J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2985 - 2987. [Full Text] [PDF]

				S. Fujii, L. Zhang, J. Igarashi, and H. Kosaka L-Arginine Reverses p47phox and gp91phox Expression Induced by High Salt in Dahl Rats Hypertension, November 1, 2003; 42(5): 1014 - 1020. [Abstract] [Full Text] [PDF]

				K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part II: Animal and Human Studies Circulation, October 28, 2003; 108(17): 2034 - 2040. [Full Text] [PDF]

				O. Jung, S. L. Marklund, H. Geiger, T. Pedrazzini, R. Busse, and R. P. Brandes Extracellular Superoxide Dismutase Is a Major Determinant of Nitric Oxide Bioavailability: In Vivo and Ex Vivo Evidence From ecSOD-Deficient Mice Circ. Res., October 3, 2003; 93(7): 622 - 629. [Abstract] [Full Text] [PDF]

				D. Gregg, F. M. Rauscher, and P. J. Goldschmidt-Clermont Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch Am J Physiol Cell Physiol, October 1, 2003; 285(4): C723 - C734. [Abstract] [Full Text] [PDF]

				M. Tepel Oxidative stress: does it play a role in the genesis of essential hypertension and hypertension of uraemia? Nephrol. Dial. Transplant., August 1, 2003; 18(8): 1439 - 1442. [Full Text] [PDF]

				M. Tepel Oxidative stress: does it play a role in the genesis of essential hypertension and hypertension of uraemia? Nephrol. Dial. Transplant., August 1, 2003; 18(88): 1439 - 1442. [Full Text]

				B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]

				K. Grote, I. Flach, M. Luchtefeld, E. Akin, S. M. Holland, H. Drexler, and B. Schieffer Mechanical Stretch Enhances mRNA Expression and Proenzyme Release of Matrix Metalloproteinase-2 (MMP-2) via NAD(P)H Oxidase-Derived Reactive Oxygen Species Circ. Res., June 13, 2003; 92 (11): e80 - e86. [Abstract] [Full Text] [PDF]

				D. G Harrison, Hua Cai, U. Landmesser, and K. K Griendling The Pickering Lecture British Hypertension Society, 10th September 2002: Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 51 - 61. [Abstract] [PDF]

				M. J Brown A RATIONAL BASIS FOR SELECTION AMONG DRUGS OF THE SAME CLASS Heart, June 1, 2003; 89(6): 687 - 694. [Full Text] [PDF]