法舒地尔对ApoE^(-/-)小鼠动脉粥样硬化斑块的影响

Anti-atherogenic effects and mechanism of fasudil on ApoE^(-/-) mice

目的观察特异性Rho激酶抑制剂法舒地尔对载脂蛋白E基因敲除(ApoE-/-)小鼠动脉粥样硬化斑块进展的影响,并探讨其可能的作用机制。方法8周龄ApoE-/-小鼠高脂饲料喂养12周后给予法舒地尔干预,12周后结束实验。将ApoE-/-小鼠随机分为三组(n=10):对照组(饮用水)、法舒地尔低剂量组(30mg·kg-1.d-1)和法舒地尔高剂量组(100mg·kg-1.d-1)。在实验结束时,测量小鼠体质量、血压及血脂水平;对头臂干动脉粥样硬化病变进行病理学检查;化学发光法及组织荧光法检测小鼠胸主动脉超氧阴离子和活性氧(ROS)。结果法舒地尔干预对ApoE-/-小鼠体质量、收缩压及血脂水平均无明显影响。与对照组相比,法舒地尔高剂量组头臂干动脉粥样硬化斑块面积和动脉内-中膜厚度(IMT)分别减少54%(P<0.01)和42%(P<0.05)。法舒地尔干预使ApoE-/-小鼠胸主动脉原位ROS的生成较对照组明显减少(P<0.01);法舒地尔高剂量组胸主动脉的超氧阴离子产量低于对照组(P<0.05)。结论阻断Rho激酶可抑制ApoE-/-小鼠头臂干动脉粥样硬化斑块的进展,其作用独立于血压和血脂水平,可能与抗氧化应激有关。

Objective To examine the effects of fasudil,a specific Rho kinase inhibitor,on atherosclerotic plaque progression in apolipoprotein E-deficient（ApoE^-/-）mice,and explore the potential mechanisms.Methods After 12 weeks of fat-feeding,ApoE^-/-mice were orally administrated with fasudil for 12 weeks.Mice were randomly allocated into three groups：control group（tap water）,low-dose fasudil group（30 mg·kg^-1·d^-1）and high-dose fasudil group（100 mg·kg^-1·d^-1）（n=10 in each group）.At the end of the study,body weight,blood pressure and blood lipid were measured,and atherosclerosis of brachiocephalic arteries were determined by histological examinations.Production of superoxide anion and reactive oxygen species（ROS）were measured in the thoracic aorta of mice using chemiluminescence and histofluorescence techniques.Results Fasudil treatment had no effect on body weight,blood pressure and blood lipid concentrations of ApoE^-/-mice.The plaque area and intima-medial thickness of brachiocephalic artery were attenuated by 54% and 42%,respectively in high-dose fasudil group in comparison with control group（P〈0.01 and P〈0.05,respectively）.Furthermore,fasudil treatment significantly reduced in situ ROS production of thoracic aorta（P〈0.01）.And the production of superoxide anion in the aortic wall was lower in high-dose fasudil group than in control group（P〈0.05）.Conclusion Blocking Rho kinase may inhibit the progression of atherosclerotic plaques of brachiocephalic arteries in ApoE^-/-mice,and the effect may be independent of blood pressure and blood lipid changes,while probably be related with the anti-oxidative stress effect.