葡萄籽原花青素与阿托伐他汀联合应用治疗动脉粥样硬化的研究

Experimental study of grape seed proanthocyanidin extract plus atorvastatin in the treatment of atherosclerosis

目的观察葡萄籽原花青素（GSPE）及阿托伐他汀对新西兰兔动脉粥样硬化基质金属蛋白酶-9（MMP-9）的影响，探讨其抗动脉粥样硬化的可能机制。方法将雄性新西兰兔30只随机分为5组，对照组饲喂标准颗粒饲料，共24周。其余各组均饲喂含1％胆固醇的颗粒饲料，12周后模型组饲喂含1％标准颗粒饲料，GSPE组饲喂含1％GSPE的颗粒饲料，阿托伐他汀组饲喂含阿托伐他汀（2．5mg·kg^-1·d6-1）的颗粒饲料，GSPE联用阿托伐他汀（联合组）饲喂含阿托伐他汀（2．5mg·kg^-1·d^-1）和1％GSPE的颗粒饲料，共12周。24周末处死全部新西兰兔，留取主动脉作常规病理观察和免疫组化染色。于实验前及实验的第12、24周末经耳中动脉采空腹血，检测血清MMP-9水平。结果模型组主动脉粥样斑块内和血清MMP-9表达均比对照组增加（均P〈0．05）。GSPE组、阿托伐他汀组、联合组与模型组比较病变轻，主动脉壁MMP-9表达减少，血清MMP-9水平下降，分别为（1．06±0．21）、（1．07±0．20）、（0．81±0．16）与（1．32±0．24）ng／ml，均P〈0．05。结论GSPE及阿托伐他汀均具有抗动脉粥样硬化效应，该效应的发挥与其抑制MMP有关，二者联合应用作用更明显。

Objective To observe the effects of grape seed proanthocyanidin extract （GSPE） plus atorvastatin treatment on matrix metalloproteinase-9 （MMP-9） in experimental atherosclerosis rabbits and to explore its mechanism. Methods Thirty male New Zealand rabbits were randomized into five groups. The normal control group were fed with standard diet for 24 weeks. And the other groups were fed with standard diet containing 1% cholesterol for 12 weeks. In the sequential 12 weeks, the model control group was fed with standard diet. The GSPE group was fed with standard diet containing 1% grape seed proanthoeyanidin（GSP）. The atorvastatin group was fed with standard diet containing atorvastatin（2.5 mg · kg^- 1 · d^-1 ）. The GSPE plus atorvastatin group was fed with standard diet containing 1%GSP and atorvastatin（2.5 mg^-1 · kg-I · d^-1 ）. Blood samples were drawn from ear middle arteries of rabbits just before the experiment and at the 12th and the 24th weekend of the experiment. All the rabbits were fasted for at least eight hours before the blood was drawn. The blood samples were analyzed for the matrix metalloproteinase-9（MMP-9）. All the rabbits were sacrificed at the 24th weekend, and the expression of MMP-9 was observed in the thoracic aortic tissue using immunohistochemistry technique. Results The serum level and aorta expression of MMP-9 were increased in model group compared to control group（all P〈0.05）. The severity of atherosclerosis was less in three drug groups than that in model control group. The GSPE, atorvastatin and GSPE plus atorvastatin groups versus model group showed less atherosclerotie lession, the decreased expression of aorta MMP-9 and the decreased serum level of MMP-9[（1.06±0.21）, （1.07 ±0.20）, （0.81±0.16） vs. （1.32±0.24）ng/ml, all P〈0.05]. The effect in the GSPE and atorvastatin group was most obvious. Conclusions GSPE plus atorvastatin group has the most efficacy of anti-atherogenesis, which is associated with its reducing the expression of matrix metalloproteinase.