氟伐他汀对家兔颈动脉粥样斑块巨噬细胞和基质金属蛋白酶的影响

目的观察高胆固醇血症家兔颈动脉粥样斑块内炎性巨噬细胞与MMP-2、MMP-9的表达情况，并研究氟伐他汀干预对巨噬细胞聚集和基质金属蛋白酶（MMPs）表达的影响，探索他汀类药物在稳定颈动脉斑块中的作用及机制。方法24只家兔随机分为对照组、高脂组和治疗组，每组8只，分别给予普通饲料、高脂饲料和高脂饲料加氟伐他汀喂养，测定不同时间点血清总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C）水平。喂养第12月时处死动物，取颈动脉进行石蜡切片，测量并计算颈动脉I／M比值，SP法进行CD68、MMP-2和MMP-9免疫组织化学染色。结果治疗组血清TC、LDL-C浓度明显低于高脂组（P〈0．01）。治疗组I／M比值明显低于高脂组（P〈0．01）。高脂组颈动脉斑块中见大量CD68阳性细胞，而治疗组CD68阳性细胞数显著少于高脂组（P〈0．01）。颈动脉斑块中MMP-2、MMP-9阳性细胞和染色强度明显增加，治疗组MMP-2和MMP-9的表达较高脂组显著减少（P=0．002和P=0．016）。结论氟伐他汀治疗可以抑制高胆固醇血症家兔颈动脉粥样斑块的形成．减轻斑块内巨噬细胞的浸润并抑制MMP-2和MMP-9的产生，从而起到稳定斑块的作用。

Effect of Fluvastatin on Macrophages and Matrix Metalloproteinases in Carotid Atherosclerotic Plaques in Rabbits

Objective To observe inflammatory macrophages and the expression of MMP-2 and MMP-9 in carotid atherosclerotic plaques in hypercholesterolemic rabbits and the effects of fluvastatin on them. To explore whether statin could stabilize carotid plaques and its possible mechanisms.Methods Twenty-four rabbits were randomly divided into three groups: Control group (n=8), hyper-lipid diet group (n=8) and therapy group (n=8). Animals in three group received normal diet, hyper-lipid diet and hyper-lipid diet with fluvastatin,respectively. Serum TC, TG, LDL-C and HDL-C level were measured at different time point. The rabbits were killed at 12 weeks. Carotid arteries were isolated and paraffin-embedded slices were performed. Intima and media thickness of carotid artery was measured and intima-to-media (I/M) ratio was calculated. Immunohistochemical staining of CD68, MMP-2 and MMP-9 antigen expression was performed with S-P method. Results Serum concentration of TC and LDL-C in therapy group was lower than that in hyper-lipid diet group P<0.01,I/M ratio in therapy group were lower than that in hyper-lipid diet group (P<0.01). There were many CD68 positive cells in carotid plaques in hyper-lipid diet group, and the number of CD68 positive cells in therapy group was less than that in hyper-lipid diet group (P<0.01). The number and intensity of MMP-2 and MMP-9 positive cells was increased in carotid plaques, and the expression of MMP-2 and MMP-9 in therapy group decreased significantly compared with hyper-lipid diet group (P=0.002 and P=0.016, respectively). Conclusion Fluvastatin therapy could prevent the formation of carotid atherosclerotic plaques in hypercholesterolemic rabbits. Fluvastatin might stabilize carotid plaques through decrease of macrophages infiltration and inhibit ion of the expression of MMP-2 and MMP-9.