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Nox2‐dependent NADPH oxidase activity contributes to atherogenesis in Apolipoprotein E‐Null (ApoE−/−) mice
Author(s) -
Drummond Grant Raymond,
Diep Henry,
Mast Anja Elizabeth,
Selemidis Stavros,
Dusting Gregory James,
Sobey Christopher Graeme,
Judkins Courtney Peta
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.35
Subject(s) - apolipoprotein e , nox4 , nadph oxidase , medicine , knockout mouse , endocrinology , reactive oxygen species , apolipoprotein b , chemistry , biology , oxidative stress , biochemistry , cholesterol , receptor , disease
Excessive production of reactive oxygen species (ROS) in the blood vessel wall is associated with many cardiovascular risk states including hypercholesterolemia. In the present study we investigated the roles of Nox2‐ and Nox4‐dependent NADPH oxidases in ROS production and atherogenesis in ApoE −/− mice fed on high‐fat diet for 7, 14 or 21 weeks. Minimal lesions were present in aortas of ApoE −/− mice at 7 (1.2±0.3%) and 14 (2.1±0.2%) weeks; however, by 21 weeks a large proportion of the aorta was covered by lesions (16.0±2.5%). No lesions developed in wild‐type (wt) mice. Nox2 protein expression was similar between strains at 7 weeks but was markedly higher in ApoE −/− versus wt at 14 (2.5‐fold; P<0.05) and 21 (6‐fold; P<0.05) weeks. By contrast, Nox4 expression was reduced by 75% in ApoE −/− mice at 21 weeks (P<0.05). Aortic ROS production was similar between strains at 7 weeks but was elevated in ApoE −/− mice at 14 (2.6‐fold) and 21 (2.2‐fold) weeks. In preliminary experiments (n=4), lesion burden in Nox2 −/− /ApoE −/− double knockout mice appeared to be ∼50% less than that in ApoE −/− mice. In conclusion, aortic Nox2 expression and ROS production is elevated in the early stages of atherogenesis in ApoE −/− mice. Together with our finding of reduced lesions in Nox2 −/− /ApoE −/− mice, these data suggest a causal role for Nox2‐oxidase in atherosclerosis, thus highlighting the enzyme as a potential therapeutic target.