Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis
Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis
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DOI：
10.1016/j.atherosclerosis.2006.05.040
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发表时间：
2007-04-01
期刊：
影响因子：
5.3
通讯作者：
Toba, Kenji
中科院分区：
文献类型：
--
作者：
Xi, Hang;Akishita, Masahiro;Toba, Kenji
目的：有效的自由基清除剂，依达拉奉，氧化应激诱导的内皮损伤和早期动脉粥样硬化的影响进行了研究，使用动物模型和培养cells.Methods和results：内皮细胞凋亡诱导5分钟动脉内暴露的大鼠颈动脉与0.01 mmol/L H2 O2。依达拉奉治疗（10 mg/kg i. p.）3天抑制内皮细胞凋亡约40%，如通过24小时时的表面样本的染色质染色所评估的。同样，依达拉奉剂量依赖性抑制H2 O2诱导的培养内皮细胞凋亡，同时抑制8-异前列腺素形成、4-羟基-2-壬烯醛（4-HNE）蓄积和VCAM-1表达。接下来，将载脂蛋白-E敲除小鼠用依达拉奉（10 mg/kg i. p.）或载体处理。依达拉奉治疗减少主动脉窦动脉粥样硬化病变（0.18 +/- 0.01至0.09 +/- 0.01 mm（2），P < 0.001）和降主动脉（5.09 +/- 0.86 ~ 1.75 +/- 10.41 mm（2），P < 0.05），通过油红O染色评价，不影响血脂浓度或血压。二氢乙锭标记和细胞色素c还原试验表明，依达拉奉抑制主动脉中的超氧阴离子。依达拉奉可降低血浆8-异前列烷浓度和主动脉硝基酪氨酸、4-HNE和VCAM-1含量。结论：依达拉奉可作为早期动脉粥样硬化的有效治疗药物，有待临床疗效的验证。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
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, apolipoprotem-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 mm(2), P < 0.001) and descending aorta (5.09 +/- 0.86 to 1.75 +/- 10.41 mm(2), 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. (c) 2006 Elsevier Ireland Ltd. All rights reserved.