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Apolipoprotein E-deficient mice (ApoE-/-) develop severe hyperlipidaemia and atherosclerotic lesions throughout the aortic root, features that are aggravated by atherogenic diets. NADPH oxidase 2 (Nox2) is an important enzymatic source of reactive oxygen species that contributes to systemic atherosclerosis in ApoE-/- mice. The aim of this study was to investigate the role of Nox2 inhibition in skeletal muscle pathophysiology and cellular oxidative stress of ApoE-/- mice administered a Western-type of diet (WD).ApoE-/- mice were maintained on either a chow or a Western diet for 12 weeks and were treated with the Nox2ds-tat inhibitor or control peptide for the last 8 weeks of feeding. Skeletal muscles and the liver were dissected for molecular, biochemical and histological analysis.Individual muscle fibres from ApoE-/- mice were significantly enlarged due to ectopic fat accumulation. There was an increase in hepatic inflammation and lipid deposition in response to WD administration. Importantly, there was perturbed gene expression for fatty acid metabolism and antioxidant genes, followed by evidence of oxidative stress, as shown by elevated lipid peroxidation and oxidative protein modifications such as carbonylation and tyrosine nitration in the skeletal muscle of WD-fed mice. Pharmacological inhibition of Nox2 decreased superoxide production and protein carbonylation, one of the most harmful protein modifications, in the muscle of ApoE-/- mice but had no effect on the liver.Our data indicate that ApoE deficiency induces oxidative damage in skeletal muscle and hepatic steatosis that are more profound under Western diet. Nox2 inhibition attenuates oxidative stress in skeletal muscle and holds promise for counteracting the impact of peripheral atherosclerosis in skeletal muscle. This study provides key evidence to better understand the pathophysiology of skeletal muscle in peripheral atherosclerosis and arterial disease; it also identifies alternative therapies to combat muscle oxidative stress.