Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice.
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 p47phox subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47phox will attenuate oxidative stress and AAA formation in Ang II-infused apoE-/- mice.


RESULTS
Male apoE-/- and apoE-/-p47phox-/- mice received saline or Ang II (1000 ng x kg(-1) x 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-/-p47phox-/- 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-/-p47phox-/- mice compared with apoE-/- mice (P < 0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoE-/-p47phox-/- mice compared with apoE-/- mice. Deletion of p47phox 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 p47phox deletion on AAA formation.


CONCLUSIONS
Deletion of p47phox attenuates Ang II-induced AAA formation in apoE-/- mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.
Thomas
Manesh
M
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.).
Gavrila
Dan
D
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.).
McCormick
Michael L
ML
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.).
Miller
Francis J
FJ
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.).
Daugherty
Alan
A
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.).
Cassis
Lisa A
LA
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.).
Dellsperger
Kevin C
KC
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.).
Weintraub
Neal L
NL
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.).
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D000316:Adrenergic alpha-Agonists; D001057:Apolipoproteins E; D014280:Triglycerides; D013481:Superoxides; D000804:Angiotensin II; D010656:Phenylephrine; D002784:Cholesterol; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020778:Matrix Metalloproteinase 2