title: 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.
  
  
  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 H(2)O(2)-induced increases in P-IKK, P-JNK, TNF-alpha, 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-kappaB and AP-1.
authors.affiliation: Oxidative Stress Group, JDRF Diabetes and Metabolism Division, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 8008, Australia.
authors.forename: Phyllis
authors.initials: P
authors.lastname: Chew
authors.forename: Derek Y C
authors.initials: DY
authors.lastname: Yuen
authors.forename: Philip
authors.initials: P
authors.lastname: Koh
authors.forename: Nada
authors.initials: N
authors.lastname: Stefanovic
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Ismail
authors.initials: I
authors.lastname: Kola
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Judy B
authors.initials: JB
authors.lastname: de Haan