NADPH oxidase 2 (Nox2) by generating reactive oxygen species (ROS) plays an important role in endothelial oxidative stress associated with obesity, insulin resistance and type-2 diabetes. In order to investigate the roles of Nox2 activation and ROS in high fat diet (HFD)-induced endothelial dysfunction and metabolic disorders, we crossed the Nox2(-/-) mice with the apolipoprotein E knockout (ApoE(-/-)) mice which is an established animal model to study dietary metabolic disorders. Littermates of ApoE(-/-) and Nox2/ApoE double knockout mice on the C57BL/6J background (6 weeks old, n = 9) were fed with HFD (45% kcal fat, 20% kcal protein and 35% kcal carbohydrate) or normal chow diet (NCD, 9.3% kcal fat, 25.9% kcal protein and 64.8% kcal carbohydrate) for 10 weeks. Body weights were measured weekly and mice were used at 16 weeks of age. Compared to age-matched NCD-fed mice, HFD ApoE(-/-) mice had hyperlipidaemia, hyperglycaemia and significant increases in body weight (NCD 27.9 ± 1.5 vs HFD 31.3 ± 1.1 g; p < 0.05). These metabolic changes were accompanied by significant increases in aorta ROS production as measured by lucigenin (5 µM)-chemiluminescence and DHE fluorescence, and a decrease in endothelium-dependent vessel relaxation to acetylcholine (Emax NCD 82.2 ± 5.5% vs HFD 68.7 ± 10.7%; p < 0.05) as assessed by an organ bath. HFD ApoE(-/-) mice had high blood pressure as compared to NCD controls (p < 0.05). Compared to ApoE(-/-) mice, Nox2/ApoE double knockout mice under the same HFD had no significant increases in levels of fasting LDL, triglyceride and glucose and their body weights were maintained at the NCD levels (NCD 29.1 ± 0.8 vs HFD 29.0 ± 0.7 g). The aorta ROS production and the endothelium-dependent vessel relaxation to acetylcholine were well preserved (Emax NCD 75.1 ± 11.0% vs HFD 78.1 ± 3.6%). HFD Nox2/ApoE double knockout mice had normal blood pressure. In conclusion, Nox2-derived oxidative stress plays an important role in the pathogenesis of dietary obesity-associated metabolic syndrome and endothelial dysfunction. Targeting Nox2-derived ROS represents a valuable therapeutic strategy to these diseases.
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