Hang Xi, Masahiro Akishita, Kumiko Nagai, Wei Yu, Hiroshi Hasegawa, Masato Eto, Koichi Kozaki and Kenji Toba
Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Japan
Objective. Effects of potent free radical scavenger, edaravone, on oxidative stress-induced endothelial damage and early atherosclerosis were investigated using animal models and cultured cells.
Methods and results. Endothelial apoptosis was induced by 5-min intra-arterial exposure of a rat carotid artery with 0.01 mmol/L H2O2. Edaravone treatment (10 mg/kg i.p.) for 3 days suppressed endothelial apoptosis, as evaluated by chromatin staining of en face specimens at 24 h, by approximately 40%. Similarly, edaravone dose-dependently inhibited H2O2-induce apoptosis of cultured endothelial cells in parallel with the inhibition of 8-isoprostane formation, 4-hydroxy-2-nonenal (4-HNE) accumulation and VCAM-1 expression. Next, apolipoprotein-E knockout mice were fed a high-cholesterol diet for 4 weeks with edaravone (10 mg/kg i.p.) or vehicle treatment. Edaravone treatment decreased atherosclerotic lesions in the aortic sinus (0.18 ± 0.01 to 0.09 ± 0.01 mm2, P < 0.001) and descending aorta (5.09 ± 0.86 to 1.75 ± 0.41 mm2, P < 0.05), as evaluated by oil red O staining without influence on plasma lipid concentrations or blood pressure. Dihydroethidium labeling and cytochrome c reduction assay showed that superoxide anions in the aorta were suppressed by edaravone. Also, plasma 8-isoprostane concentrations and aortic nitrotyrosine, 4-HNE and VCAM-1 contents were decreased by edaravone treatment.
Conclusions. These results suggest that edaravone may be a useful therapeutic tool for early atherosclerosis, pending the clinical efficacy.
Keywords: Atherosclerosis; Reactive oxygen species; Free radical scavenger; Edaravone; 4-HNE; Apolipoprotein E knockout mouse
Atherosclerosis
Volume 191, Issue 2 , April 2007, Pages 281-289
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