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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:823.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Site-Specific Antiatherogenic Effect of the Antioxidant Ebselen in the Diabetic Apolipoprotein E–Deficient Mouse

Phyllis Chew; Derek Y.C. Yuen; Philip Koh; Nada Stefanovic; Mark A. Febbraio; Ismail Kola; Mark E. Cooper; Judy B. de Haan

From the Oxidative Stress Group (P.C., N.S., J.B.d.H.), Diabetic Complications Group (P.K., M.E.C.), JDRF Diabetes and Metabolism Division, Cellular & Molecular Metabolism Laboratory (D.Y.C.Y., M.A.F.), Metabolism & Obesity Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; and the Schering-Plough Research Institute (I.K.), Schering-Plough Corporation, Kenilworth, NJ.

Correspondence to Judy B. de Haan, Head, Oxidative Stress Group, JDRF Diabetes and Metabolism Division, Baker IDI Heart and Diabetes Institute, PO Box 6492 St Kilda Rd Central, Melbourne, VIC 8008, Australia. E-mail judy.dehaan{at}bakeridi.edu.au

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-, 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-B and AP-1.

Ebselen-gavage of diabetic apoE^–/– mice led to site-specific lesional reductions within most regions of the aorta but not within the aortic sinus. Where reductions occurred, ebselen also lowered oxidative stress and proatherogenic RAGE and VEGF. Based on our results, ebselen may be effective as an antiatherogenic therapy in diabetic macrovascular disease.

Key Words: cardiovascular diseases • atherosclerosis • diabetes mellitus • antioxidants • ebselen