Site-specific antiatherogenic effect of the antioxidant ebselen in the diabetic apolipoprotein E-deficient mouse

Abstract

OBJECTIVE-: Recently we showed that lack of the antioxidant enzyme glutathione peroxidase-1 (GPx1) accelerates atherosclerosis and upregulates proatherogenic pathways in diabetic apoE/GPx1-deficient double-knockout mice, thereby establishing GPx1 as an important therapeutic target. In vivo studies now investigate ebselen, a seleno-organic GPx1-mimetic, for its potential to reduce diabetes-associated atherosclerosis. METHODS AND RESULTS-: Lesions were significantly increased in diabetic apoE aortas (P<0.001) compared with nondiabetic controls after 20 weeks of diabetes. Ebselen-gavage significantly reduced total aortic lesions (P<0.001), with significant regional reductions in the arch (P<0.001), thoracic (P<0.001), and abdominal regions (P<0.05), but not within the aortic sinus of diabetic apoE mice. These reductions were accompanied by significantly lower nitrotyrosine and Nox2 levels, reduced proatherogenic cellularity (macrophages and SMCs), and reduced expression of the proatherogenic mediator RAGE. Within the aortic sinus, ebselen reduced nitrotyrosine, Nox2, and VEGF levels but had no effect on RAGE. Studies in HAECs show that ebselen abrogates H2O2-induced increases in P-IKK, P-JNK, TNF-α, and Nox2. CONCLUSIONS-: Ebselen reduces atherosclerotic lesions in most regions of diabetic apoE aorta, except within the aortic sinus, suggesting its effectiveness as a potential antiatherogenic therapy in diabetic- macrovascular disease. Ebselen may elicit its effect via modulation of transcription factors such as NF-κB and AP-1. © 2009 American Heart Association, Inc.