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. 2011 Jun;216(2):321-6.
doi: 10.1016/j.atherosclerosis.2011.02.028. Epub 2011 Feb 24.

Role for Nox1 NADPH oxidase in atherosclerosis

Andrea L Sheehan  1 , Samuel Carrell, Bryon Johnson, Bojana Stanic, Botond Banfi, Francis J Miller Jr
Affiliations

Role for Nox1 NADPH oxidase in atherosclerosis

Andrea L Sheehan et al. Atherosclerosis. 2011 Jun.

Abstract

Objective: Examine the contribution of Nox1 NADPH oxidase to atherogenesis.

Methods and results: Male apolipoprotein E deficient mice (ApoE(-/-)) and male mice deficient in both apolipoprotein E and Nox1 (ApoE(-/-) Nox1(-/y)) received an atherogenic diet for 18 weeks. Mean blood pressures, body weights, and serum cholesterol levels were similar between the two groups of mice. Deficiency of Nox1 decreased superoxide levels and reduced lesion area in the aortic arch from 43% (ApoE(-/-)) to 28% (ApoE(-/-) Nox1(-/y)). The reduction in lesion size at the level of the aortic valve in ApoE(-/-)/Nox1(-/y) was accompanied by a decrease in macrophage infiltration as compared to ApoE(-/-) mice. Carotid artery ligation in ApoE(-/-) mice induced accelerated intimal hyperplasia with decreased cellular proliferation and increased collagen content in the neointima of vessels deficient in Nox1.

Conclusions: Nox1-derived ROS modify lesion composition and contribute to lesion size in a murine model of atherosclerosis.

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Figures

Figure 1
Figure 1. The absence of Nox1 reduces lesion size
(A) Photomicrographs of proximal and distal aorta following oil red O staining. (B) Percent lesion area (oil red O area/total area) in three distinct regions of the aorta (n=11–16). (C) Photomicrographs of sections at level of aortic valve after immunostaining with MOMA-2. (D) Quantitation of lesion area on the aortic valve leaflets (mm2/leaflet perimeter2, n=7–9). (E) Positive MOMA stain normalized to lesion area on the aortic valve (n=8–9). A−/N+=ApoE−/− Nox1+/y; A−/N−=ApoE−/− Nox1−/y, *p<0.05.
Figure 2
Figure 2. Superoxide levels are reduced in Nox1-deficient atherosclerotic aorta
(A) Superoxide levels, measured by lucigenin-enhanced chemiluminescence normalized to vessel surface area (RLU/sec/mm2, n=7–9; *p<0.05 vs. WT; Δ p<0.05 vs. A−/N+). (B) Confocal fluorescent images of aorta after DHE staining. Arrows identify endothelium. Scale bar=100 µm. (C) Lipid peroxidation measured by MDA levels (nmol/mg protein) in hearts (n=6; *p<0.05 vs. WT).
Figure 3
Figure 3. Effect of Nox1 deletion on response to carotid ligation
(A) Representative cross sections of carotid arteries 28 days after ligation; sections were stained with VVG to identify elastic lamina and counterstained with eosin. Arrow identifies the internal elastic lamina. Scale bar=200 µm. (B) Ratio of intima and medial areas at 0.5 and 1.0 mm proximal to the carotid ligation (n=10–14; *p<0.05 vs. WT). (C) Perimeter of external elastic lamina (mm) in the injured (left carotid) and non-injured (right carotid) arteries (n=10–14; *p<0.05 vs. WT).
Figure 4
Figure 4. Role of Nox1 in lesion composition after carotid injury
(A) Proliferation index as measured by number of Ki-67 positive cells relative to total number of cells within the intima of carotid arteries 28 days after ligation (n=8–10; *p<0.05). Scale bar=200 µm. (B) Collagen staining with Sirius red by polarized light, normalized to intimal area (n=12; *p<0.05). When viewed with polarized light, collagen fibers appear bright yellow or orange.
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