奥美沙坦酯对载脂蛋白E基因敲除小鼠动脉粥样硬化的影响

Impact of olmesartan medoxomil on atherosclerosis lesions in apolipoprotein E knockout mice

目的探讨奥美沙坦酯对载脂蛋白E基因敲除（ApoE^-/-）小鼠动脉粥样硬化病变的抑制作用及可能机制。方法16只6周龄雄性ApoE^-/-）小鼠随机分为动脉粥样硬化模型组和干预组，干预组在高脂饲料喂养同时予以奥美沙坦酯（10mg·kg^-1·day^-1）灌胃治疗。8只C57BL／6小鼠为对照组，给予普通饲料。12周后行血压、血脂测定；主动脉油红“O”染色、苏木素一伊红（HE）染色、Elasticavan Gieson’S（EVG）染色、苦味酸一天狼猩红（PSR）染色分别观察斑块面积、斑块形态、弹性纤维及胶原蛋白含量；免疫组织化学方法检测斑块内组织蛋白酶S（CatS）、仪平滑肌肌动蛋白（ASMA）、巨噬细胞表面分子．3（Mac-3）表达。结果模型组总胆固醇、低密度脂蛋白水平均高于对照组[（15．08±1．64）比（2．06±0．15）mmol／L、（15．60±1．05）比（0．004-0．00）mmol／L]（均P〈0．01），三酰甘油水平与对照组相比差异无统计学意义。模型组主动脉组织内可见明显动脉粥样硬化斑块形成，CatS、ASMA及Mac-3表达均高于对照组。干预组血压、血脂水平与模型组相比差异无统计学意义，但主动脉粥样斑块面积明显减少（P〈0．05），CatS、Mac-3的表达低于模型组[（2．4±1．2）％比（8．8±3．2）％、（2．2±1．2）％比（7．2±2．8）％]（均P〈0．01），而胶原蛋白、弹性纤维含量及ASMA的表达均多于模型组（P〈0．05）。结论奥美沙坦酯可以抑制动脉粥样硬化病变形成，其机制可能与抑制斑块中CatS的表达和炎症反应，增加其弹性纤维和胶原蛋白含量有关。

Objective To investigate the effect and possible mechanisms of olmesartan medoxomil on atherosclerosis of apolipoprotein E knockout （ApoE-/- ） mice. Methods Sixteen 6-week-old male ApoE -/- mice were randomly divided into atherosclerosis model group fed with high fat diet, and olmesartan medoxomil intervention group fed with high fat diet and olmesartan medoxomil （10 mg· kg^-1· day^-1, per garage）. Eight C57BL/6 mice were fed with normal diet, and treated for 12 weeks. The blood pressure and the serum level of lipid were detected ; the aorta were removed, oil red staining for plaque area, Hematoxylin and eosin （HE） staining for plaque morphology, Elastica van Gieson （EVG） staining for elastin, and picrosirius red （PSR） for collagen respectively; and the expression of cathepsin S （Cat S）, smooth action protein （ASMA） and macrophage surface molecule-3 （Mac-3） were detected by immunohistochemisty analysis. Results Serum cholesterol and low density lipoprotein levels were significantly higher in atherosclerosis model group than in control group[ （ 15.08 ＋- 1.64） vs （2.06 -＋ 0. 15） retool/L, （ 15.60± 1.05） vs （0. 00 ± 0. 00） mmol/L] （ all P 〈 0. 01 ）, while triglyceride level was similar between the two group. In contrast to model group, the mice in intervention group showed no statistical difference in blood pressure and plasma lipid levels, while the plaque areas in the aorta were significantly decreased （ P 〈 0.05 ） as well as the expression of Cat S and Mac-3[（2.4-＋1.2） vs （8.8 ＋3.2）%,（2.2 ＋1.2） vs （7.2 -＋ 2. 8）% ] （all P 〈 0. 01 ）. In addition, the elastin levels, collagen contents, and the expression of ASMA remained significantly higher compared with model group （P 〈 0. 05）. Conclusion Olmesartan medoxomil could slow down the atherosclerosis process, the possible mechanism was implicated with the suppression of Cat S and decreased inflammatory responses alongside the increased elastin and collagen contents.