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(Circulation. 2006;114:404-413.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Deletion of p47^phox Attenuates Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E–Deficient Mice

Manesh Thomas, MD^*; Dan Gavrila, MD^*; Michael L. McCormick, PhD; Francis J. Miller, Jr, MD; Alan Daugherty, PhD, DSc; Lisa A. Cassis, PhD; Kevin C. Dellsperger, MD, PhD; Neal L. Weintraub, MD

From the Department of Internal Medicine (M.T., M.L.M., D.G., F.J.M., N.L.W.) and Free Radical and Radiation Biology Program, Department of Radiation Oncology (M.L.M., F.J.M., N.L.W.), University of Iowa, Iowa City; Veteran’s Administration Medical Center, Iowa City, Iowa (N.L.W.); Department of Internal Medicine (A.D.) and Graduate Center for Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Department of Internal Medicine, University of Missouri, Columbia (K.C.D.).

Correspondence to Dr Neal L. Weintraub, Department of Internal Medicine, University of Iowa, College of Medicine, 200 Hawkins Dr, E-315GH, Iowa City, IA 52242. E-mail neal-weintraub{at}uiowa.edu

Received December 8, 2005; revision received May 25, 2006; accepted May 30, 2006.

Background— Angiotensin II (Ang II) contributes to vascular pathology in part by stimulating NADPH oxidase activity, leading to increased formation of superoxide (O₂^–). We reported that O₂^– levels, NADPH oxidase activity, and expression of the p47^phox subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47^phox will attenuate oxidative stress and AAA formation in Ang II–infused apoE^–/– mice.

Methods and Results— Male apoE^–/– and apoE^–/–p47^phox–/– mice received saline or Ang II (1000 ng · kg^–1 · min^–1) infusion for 28 days, after which abdominal aortic weight and maximal diameter were determined. Aortic tissues and blood were examined for parameters of aneurysmal disease and oxidative stress. Ang II infusion induced AAAs in 90% of apoE^–/– versus 16% of apo^–/–p47^phox–/– mice (P<0.05). Abdominal aortic weight (14.1±3.2 versus 35.6±9.0 mg), maximal aortic diameter (1.5±0.2 versus 2.4±0.4 mm), aortic NADPH oxidase activity, and parameters of oxidative stress were reduced in apoE^–/–p47^phox–/– mice compared with apoE^–/– mice (P<0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoE^–/–p47^phox–/– mice compared with apoE^–/– mice. Deletion of p47^phox attenuated the pressor response to Ang II; however, coinfusion of phenylephrine with Ang II, which restored the Ang II pressor response, did not alter the protective effects of p47^phox deletion on AAA formation.

Conclusions— Deletion of p47^phox attenuates Ang II–induced AAA formation in apoE^–/– mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.

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