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Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques.

Quesada, IM; Lucero, A; Amaya, C; Meijles, DN; Cifuentes, ME; Pagano, PJ; Castro, C (2015) Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques. Atherosclerosis, 242 (2). pp. 469-475. ISSN 1879-1484
SGUL Authors: Meijles, Daniel Nathan

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BACKGROUND: A variety of NADPH oxidase (Nox) isoforms including Noxs 1, 2, 4 and 5 catalyze the formation of reactive oxygen species (ROS) in the vascular wall. The Nox2 isoform complex has arguably received the greatest attention in the progression of atherogenesis in animal models. Thus, in the current study we postulated that specific Nox2 oxidase inhibition could reverse or attenuate atherosclerosis in mice fed a high-fat diet. METHODS: We evaluated the effect of isoform-selective Nox2 assembly inhibitor on the progression and vascularization of atheromatous plaques. Apolipoprotein E-deficient mice (ApoE-/-) were fed a high fat diet for two months and treated over 15 days with Nox2ds-tat or control sequence (scrambled); 10 mg/kg/day, i.p. Mice were sacrificed and superoxide production in arterial tissue was detected by cytochrome C reduction assay and dihydroethidium staining. Plaque development was evaluated and the angiogenic markers VEGF, HIF1-α and visfatin were quantified by real time qRT-PCR. MMP-9 protein release and gelatinolytic activity was determined as a marker for vascularization. RESULTS: Nox2ds-tat inhibited Nox-derived superoxide determined by cytochrome C in carotid arteries (2.3 ± 0.1 vs 1.7 ± 0.1 O2(•-) nmol/min*mg protein; P < 0.01) and caused a significant regression in atherosclerotic plaques in aorta (66 ± 6 μm(2) vs 37 ± 1 μm(2); scrmb vs. Nox2ds-tat; P < 0.001). Increased VEGF, HIF-1α, MMP-9 and visfatin expression in arterial tissue in response to high-fat diet were significantly attenuated by Nox2ds-tat which in turn impaired both MMP-9 protein expression and activity. CONCLUSION: Given these results, it is quite evident that selective Nox inhibitors can reverse vascular pathology arising with atherosclerosis.

Item Type: Article
Additional Information: © 2015. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Keywords: Oxidative stress, Vascular Nox, Vulnerable plaque, Animals, Aorta, Apolipoproteins E, Carotid Arteries, Cytochromes c, Cytokines, Diet, High-Fat, Disease Progression, Enzyme Inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Matrix Metalloproteinase 9, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidase 2, NADPH Oxidases, Neovascularization, Pathologic, Nicotinamide Phosphoribosyltransferase, Oxidants, Oxidative Stress, Plaque, Atherosclerotic, Reactive Oxygen Species, Regression Analysis, Vascular Endothelial Growth Factor A, Aorta, Carotid Arteries, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Disease Progression, Neovascularization, Pathologic, Reactive Oxygen Species, Cytochromes c, Vascular Endothelial Growth Factor A, Apolipoproteins E, Membrane Glycoproteins, Cytokines, Enzyme Inhibitors, Oxidants, Regression Analysis, Oxidative Stress, Male, Hypoxia-Inducible Factor 1, alpha Subunit, Matrix Metalloproteinase 9, Nicotinamide Phosphoribosyltransferase, Plaque, Atherosclerotic, Diet, High-Fat, NADPH Oxidase 2, NADPH Oxidases, Vascular Nox, Vulnerable plaque, Oxidative stress, 1103 Clinical Sciences, 1102 Cardiovascular Medicine And Haematology, Cardiovascular System & Hematology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Atherosclerosis
ISSN: 1879-1484
Language: eng
October 2015Published
8 August 2015Published Online
6 August 2015Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Project IDFunderFunder ID
PubMed ID: 26298737
Web of Science ID: WOS:000361509000013
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