Diphenyl diselenide differently modulates cardiovascular redox responses in young adult and middle-aged low-density lipoprotein receptor knockout hypercholesterolemic mice Gianni Mancini a , Jade de Oliveira a , Mariana Appel Hort a , Eduardo Luiz Gasnhar Moreira a,b , Rosa Maria Ribeiro-do-Valle b , João Batista Texeira Rocha c and Andreza Fabro de Bem a a Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil, b Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil and c Departamento de Bioquímica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil Keywords age; diphenyl diselenide; glutathione; hypercholesterolemia; oxidative stress Correspondence Andreza Fabro de Bem, Departamento de Bioquímica, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil. E-mail: andrezadebem@ccb.ufsc.br Received May 27, 2013 Accepted September 24, 2013 doi: 10.1111/jphp.12167 Abstract Objectives The present work aimed to investigate the effect of (PhSe)2 on cardio- vascular age-related oxidative stress in hypercholesterolemic mice. Methods To this end, LDL receptor knockout (LDLr −/− ) mice, 3 months (young adult) and 12 months (middle-aged) old, were orally treated with (PhSe)2. Key findings Hypercholesterolemia, regardless of age, impaired the mitochon- drial antioxidant defence in the cardiac tissue, which was characterized by a decline in mitochondrial aortic glutathione (GSH) levels and increased reactive oxygen species production in the heart. (PhSe)2 treatment improved GSH levels, thioredoxin reductase (TRxR) and GSH reductase (GR) activity, and decreased malondialdehyde levels in the heart of young adult LDLr −/− mice. Moreover, (PhSe)2 increased GPx activity in both age groups, and GR activity in the aorta of middle-aged LDLr −/− mice. Conclusions Therefore, (PhSe)2 enhances the antioxidant defences in the cardio- vascular system of LDLr −/− mice, which could explain its success as an anti- atherogenic compound. Introduction Cardiovascular disease (CVD), owing to atherosclerosis, is the leading cause of morbidity and mortality in Western countries. Atherosclerosis induces CVD through slowly pro- gressing lesion formation and luminal narrowing of the arteries. Upon plaque rupture and thrombosis, CVD mani- fests as acute coronary syndrome, myocardial infarction or stroke. [1] The underlying pathology is characterized by a chronic inflammatory disease of the arteries, initiated by endothelial dysfunction and accumulation of monocyte- derived macrophage-like foam cells in the intima. [2] Several lines of evidence point to oxidative stress as a pivotal pathophysiological mediator that leads to athero- sclerosis. Indeed, excessive production of reactive oxygen species (ROS) mediates various signalling pathways that are involved at all stages of atherosclerosis, acting as a trigger for endothelial dysfunction and ultimately, plaque rupture. [3,4] Some authors perceive atherosclerosis as an aging-related vasculopathy, wherein excessive ROS generation cannot be counteracted by native defence mechanisms. [5] Glutathione (GSH) is an abundant intracellular antioxi- dant, providing the vascular cells important protection against oxidative damage. It can react with oxidizing species, inorganic and organic peroxides, and counteract lipoprotein oxidation. [6] Moreover, the antioxidant enzymes responsible for detoxified peroxides, such as GSH peroxidase (GPx), peroxiredoxin and catalase, play a central role in protecting cardiovascular cells against oxidative damage. [7] GPx is the main antioxidant enzyme in vascular parietal cells. [8–12] Reduced GPx-1 activity has been reported in the red blood cells of patients with prevalent atheroscle- rosis. [8] Moreover, GPx-1 deficiency accelerates and modifies And Pharmacology Journal of Pharmacy Research Paper © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–•• 1