- 作者：Keisuke Morimoto ; MD ; Tomomi Hasegawa ; MD ; PhD ; Akiko Tanaka ; MD ; Bao Wulan ; MD ; Jie Yu ; MD ; Naoto Morimoto ; MD ; PhD ; Yutaka Okita ; MD ; PhD ; Kenji Okada ; MD ; PhD ; kokada@med.kobe-u.ac.jp
- 刊名：Journal of Vascular Surgery
- 出版年：2012
- 期刊代码：214_07415214
- 类别：med
- 出版时间：June, 2012
- 卷：55
- 期：6
- 页码：1749-1758
- 文件大小：3118 K
Objective
An ideal pharmaceutical treatment for abdominal aortic aneurysm (AAA) is to prevent aneurysm formation and development (further dilatation of pre-existing aneurysm). Recent studies have reported that oxidative stress with reactive oxygen species (ROS) is crucial in aneurysm formation. We hypothesized that edaravone, a free-radical scavenger, would attenuate vascular oxidative stress and inhibit AAA formation and development.Methods
An AAA model induced with intraluminal elastase and extraluminal calcium chloride was created in 42 rats. Thirty-six rats were divided three groups: a low-dose (group LD; 1 mg/kg/d), high-dose (group HD; 5 mg/kg/d), and control (group C, saline). Edaravone or saline was intraperitoneally injected twice daily, starting 30 minutes before aneurysm preparation. The remaining six rats (group DA) received a delayed edaravone injection (5 mg/kg/d) intraperitoneally, starting 7 days after aneurysm preparation to 28 days. AAA dilatation ratio was calculated. Pathologic examination was performed. ROS expression was semi-quantified by dihydroethidium staining and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining.
Results
At day 7, ROS expression and 8-OHdG-positive cells in aneurysm walls were decreased by edaravone treatment (ROS expression: 3.0 卤 0.5 in group LD, 1.7 卤 0.3 in group HD, and 4.8 卤 0.7 in group C; 8-OHdG-positive cells: 106.2 卤 7.8 cells in group LD, 64.5 卤 7.7 cells in group HD, and 136.6 卤 7.4 cells in group C; P < .0001), compared with group C. Edaravone treatment significantly reduced messenger RNA expressions of cytokines and matrix metalloproteinases (MMPs) in aneurysm walls (MMP-2: 1.1 卤 0.5 in group LD, 0.6 卤 0.1 in group HD, and 2.3 卤 0.4 in group C; P < .001; MMP-9: 1.2 卤 0.1 in group LD, 0.2 卤 0.6 in group HD, and 2.4 卤 0.2 in group C; P < .001). At day 28, aortic walls in groups LD and HD were less dilated, with increased wall thickness and elastin content than those in group C (dilatation ratio: 204.7%卤 16.0%in group C, 156.5%卤 6.6%in group LD, 136.7%卤 2.0%in group HD; P < .0001). Delayed edaravone administration significantly prevented further aneurysm dilatation, with increased elastin content (155.2%卤 2.9%at day 7, 153.1%卤 11.6%at day 28; not significant).
Conclusions
Edaravone inhibition of ROS can prevent aneurysm formation and expansion in the rat AAA model. Free-radical scavenger edaravone might be an effective pharmaceutical agent for AAA in clinical practice.