法舒地尔抗动脉粥样硬化作用及其机制  

Anti-atherogenic effect of fasudil and its mechanisms

作　　者：武多娇[1] 张怡[2,3] 高平进[2,3] 朱鼎良[2,3] 

机构地区：[1]复旦大学附属中山医院实验研究中心,上海200032 [2]上海市高血压研究所,上海200025 [3]上海市血管生物学重点实验室,上海200025

出　　处：《中国临床药学杂志》2010年第2期69-74,共6页Chinese Journal of Clinical Pharmacy

基　　金：国家科技部973和863课题(2004CB518600;2009CB521905和2006AA02Z179);上海交通大学博士创新基金(BXJ0835)

摘　　要：目的观察Rho激酶抑制剂法舒地尔对于载脂蛋白E基因敲除(apoE-KO)小鼠动脉粥样硬化(AS)不同时期的作用。方法实验包括两个治疗时间点:小鼠高脂饲料喂养同时或12周后给予法舒地尔(30 mg.kg-1.d-1,100 mg.kg-1.d-1)药物干预,药物溶于饮用水中,每个时间点设立无药物干预的小鼠为对照组(每组n=10)。采用病理学和显微超声(UBM)方法检查小鼠血管形态。结果实验结束时各组小鼠的体质量、血压、血脂无明显差异。UBM和组织学检查显示与对照组相比,法舒地尔可显著减少小鼠头臂干动脉早期AS斑块大小(P<0.05)。而在延迟干预实验中,仅高剂量的法舒地尔(100 mg.kg-1.d-1)可抑制斑块的进展,并且显示出更强地抑制斑块处巨噬细胞聚集的作用(vs对照组,P<0.05)。法舒地尔治疗(30 mg.kg-1.d-1,100 mg.kg-1.d-1)可减少小鼠胸主动脉组织原位活性氧(ROS)的产量(所有P均<0.01),而高剂量组(100 mg.kg-1.d-1)小鼠胸主动脉的超氧阴离子含量低于对照组(P=0.07)。结论本实验运用新的显微超声方法发现阻断Rho激酶可抑制apoE-KO小鼠头臂干动脉AS的形成和进展,其作用独立于血压和血脂水平,可能与法舒地尔抗氧化应激和减少损伤处巨噬细胞聚集的作用有关。AIM To examine the effect of fasudil, a specific inhibitor of Rho kinase on different stages of atherosclerosis in apolipoprotein-E knockout （apoE-KO） mice. METHODS This study included two different treatment schedules： fasudil （30 mg·kg^-1·d^-1, 100mg·kg^-1·d^-1） were given to mice at the commencement of high-fat diet feeding or 12 weeks later in tap water. Mice without fasudil in tap water were set as control in each schedule. Using ultrasound biomicroscopy （UBM） combined with histopathologic assessment to study vascular morphology of mice. RESULTS There was no significant difference between groups in body weights, arterial blood pressures, plasma cholesterol levels at the end of the study. The combined results showed fasudil reduced early atherosclerotic lesion size in the brachiocephalic arteries of mice in comparison with control group （all P 〈 0.05）. However, in delayed- treatment study, the progression of plaque was inhibited only by high-dose fasudil （ 100mg·kg^-1·d^-1 ） and fasudil （ 100 mg·kg^-1·d^-1 ） showed stronger effect on inhibiting macrophage accumulation in plaque （ vs control, P 〈 0.05）. Fasudil treatment （30 mg·kg^-1·d^-1, 100mg·kg^-1·d^-1） significantly reduced in situ reactive oxygen species（ROS） production in the thoracic aortas of mice （all P 〈0.01）. And the production of superoxide anion in the aortic wall was lower in the high-dose fasudil treatment group （100 mg·kg^-1·d^-1） than the control group（P =0.07）. CONCLUSION The study shows that blocking Rho kinase reduces both the formation and progression of atherosclerotic plaques in apoE-KO mice brachiocephalic arteries by using a novel micro-ultrasound approach. And the effect is independent of blood pressure and blood lipid changes but probably related with its effect of anti-oxidative stress and decreasing macrophages accumulation in lesions.

关 键 词：法舒地尔 动脉粥样硬化 显微超声 氧化应激 小鼠 

分 类 号：R96[医药卫生—药理学]