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 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.
