Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice

Manesh Thomas, Dan Gavrila, Michael L. McCormick, Francis J. Miller, Alan Daugherty, Lisa A. Cassis, Kevin C Dellsperger, Neal Lee Weintraub

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

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 subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47 will attenuate oxidative stress and AAA formation in Ang II-infused apoE mice. METHODS AND RESULTS - Male apoE and apoEp47 mice received saline or Ang II (1000 ng·kg·min) 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 apop47 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 apoEp47 mice compared with apoE mice (P<0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoEp47 mice compared with apoE mice. Deletion of p47 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 deletion on AAA formation. CONCLUSIONS - Deletion of p47 attenuates Ang II-induced AAA formation in apoE mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.

Original languageEnglish (US)
Pages (from-to)404-413
Number of pages10
JournalCirculation
Volume114
Issue number5
DOIs
StatePublished - Aug 1 2006

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Abdominal Aortic Aneurysm
Apolipoproteins E
Angiotensin II
NADPH Oxidase
Oxidative Stress
Weights and Measures
Matrix Metalloproteinase 2
Phenylephrine
Superoxides
Blood Vessels
Macrophages
Pathology

Keywords

  • Aneurysm
  • Aorta
  • Cardiovascular diseases
  • Free radicals
  • Inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. / Thomas, Manesh; Gavrila, Dan; McCormick, Michael L.; Miller, Francis J.; Daugherty, Alan; Cassis, Lisa A.; Dellsperger, Kevin C; Weintraub, Neal Lee.

In: Circulation, Vol. 114, No. 5, 01.08.2006, p. 404-413.

Research output: Contribution to journalArticle

Thomas, M, Gavrila, D, McCormick, ML, Miller, FJ, Daugherty, A, Cassis, LA, Dellsperger, KC & Weintraub, NL 2006, 'Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice', Circulation, vol. 114, no. 5, pp. 404-413. https://doi.org/10.1161/CIRCULATIONAHA.105.607168
Thomas, Manesh ; Gavrila, Dan ; McCormick, Michael L. ; Miller, Francis J. ; Daugherty, Alan ; Cassis, Lisa A. ; Dellsperger, Kevin C ; Weintraub, Neal Lee. / Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. In: Circulation. 2006 ; Vol. 114, No. 5. pp. 404-413.
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T1 - Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice

AU - Thomas, Manesh

AU - Gavrila, Dan

AU - McCormick, Michael L.

AU - Miller, Francis J.

AU - Daugherty, Alan

AU - Cassis, Lisa A.

AU - Dellsperger, Kevin C

AU - Weintraub, Neal Lee

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N2 - 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 subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47 will attenuate oxidative stress and AAA formation in Ang II-infused apoE mice. METHODS AND RESULTS - Male apoE and apoEp47 mice received saline or Ang II (1000 ng·kg·min) 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 apop47 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 apoEp47 mice compared with apoE mice (P<0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoEp47 mice compared with apoE mice. Deletion of p47 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 deletion on AAA formation. CONCLUSIONS - Deletion of p47 attenuates Ang II-induced AAA formation in apoE mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.

AB - 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 subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47 will attenuate oxidative stress and AAA formation in Ang II-infused apoE mice. METHODS AND RESULTS - Male apoE and apoEp47 mice received saline or Ang II (1000 ng·kg·min) 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 apop47 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 apoEp47 mice compared with apoE mice (P<0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoEp47 mice compared with apoE mice. Deletion of p47 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 deletion on AAA formation. CONCLUSIONS - Deletion of p47 attenuates Ang II-induced AAA formation in apoE mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.

KW - Aneurysm

KW - Aorta

KW - Cardiovascular diseases

KW - Free radicals

KW - Inflammation

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