Abstract 8710: A Crucial Role of Nox2 In Middle-Age Obese-Related Hyperglycaemia and Endothelial Dysfunction in Mice

Abstract

Middle-age obese is often associated with multiple organ oxidative stress and is a major risk factor for the development of cardiovascular diseases. In this study, we investigated the role of Nox2, a superoxide-generating enzyme, in a mouse model of high fat diet-induced middle-age metabolic disorders and vascular dysfunction. Littermates of C57BL/J6 wild-type and Nox2 knockout mice (7 m old, n=10) were fed with high fat diet (HFD, 45% kcal fat, 20% kcal protein and 35% kcal carbohydrate) or normal chow diet (NCD, 12% kcal fat, 28% kcal protein and 60% kcal carbohydrate) for 16 weeks, and were used at 11 m of age Compared to age-matched NCD-fed mice, wild-type mice fed with HFD showed significant increases in body weight (NCD 42±2.3 vs HFD 56±3.2g) and the levels of fasting glucose (NCD 7.4±3.3 vs HFD 8.8±2.2 mM). These metabolic changes were accompanied by significant increases (42±5%) in NADPH-dependent ROS production by aortas as measured by lucigenin-chemiluminescence, and a decrease in endothelium-dependent vessel relaxation to acetylcholine (Emax NCD 80.45±7.39% vs HFD 74.41±1.74%) as assessed by an organ bath. The systolic BP was also significantly elevated (NFD 127±8 vs HFD 142±12mmHg) (all P<0.05). Compared to WT mice, Nox2 knockout mice fed with HFD had similar scale of increase in body weight (NCD 38±3.6 vs HFD 49±2.6g, P<0.05). However, there was no significant increase in the levels of fasting glucose (NCD 7.5±0.8 vs HFD 6.7±1.5 mM). The aortic NADPH-dependent ROS production remained unchanged and the endothelium- dependent vessel relaxation to acetylcholine was well preserved (Emax NCD 80.53±11.3 vs HFD 78.18±5.6%). There was no significant increase in systolic BP (NCD 123±14 vs HFD130±9mmHg) in HFD-fed Nox2 knockout mice. In conclusion, Nox2 and Nox2-derived ROS play a key role in mediating dietary obesity-related hyperglycaemia and endothelial dysfunction after middle-age, and Nox2 may present a therapeutic target for the prevention and treatment of these diseases.