Nox2-derived oxidative stress and ageing-associated metabolic disorders and vascular dysfunction

S Cahill-Smith, JM Li. University of Surrey, Guildford, UK

Ageing has been recognised to be a major risk factor for the development of cardiovascular disease and growing evidence suggests a role for oxidative stress. NADPH oxidase 2 has been reported to be a major source of reactive oxygen species (ROS) generation in the cardiovascular system, however, the role of this enzyme in age-related metabolic disorders and vascular diseases remains unclear. In this study we used age-matched wild-type (WT) and Nox2-deficient (Nox2-/-) male mice on a C57BL/6 background at young (3-4 month) and old-age (20-24 month) with group sizes of ≥6 mice to investigate the role of Nox2 in age-related oxidative stress, metabolic disorders and vascular dysfunction. Insulin and glucose levels, blood pressure, vascular function, superoxide production and Nox2 expression were measured as described previously [1] and comparisons were made by two-way anova with Bonferroni post-hoc test. Compared to young mice, there were age-related increases in fasting serum levels of insulin and glucose and a delayed clearance of glucose in WT ageing mice (p<0.05). WT ageing mice had increased blood pressure (BP, 126 ± 3 mmHg for young and 148 ± 4 mmHg for ageing p<0.05) and this was accompanied with a significant increase in aortic ROS production as measured by DHE fluorescence (71 ± 8 AU for young and 117 ± 8 AU for ageing p<0.05), increased endothelial Nox2 expression as detected by immunofluorescence and a significant decrease in the endothelium-dependent relaxation to acetylcholine in WT ageing aortas as assessed by an organ bath (Emax 72 ± 2 % for young and 64 ± 1 % for ageing, p<0.05). However, all these ageing-related abnormalities were significantly reduced in Nox2-/- ageing mice (BP 126 ± 3 mmHg; DHE 85 ± 5 AU; Emax 79 ± 3 %: p<0.05 versus WT ageing).In conclusion, Nox2-derived oxidative stress plays an important role in ageing-associated metabolic disorders and vascular dysfunction, and targeting Nox2 represents a valuable therapeutic strategy to treat these ageing-related diseases.

[1] Du J et al, Br J Pharmacol 170:1064, 2013