氯沙坦对载脂蛋白E基因缺陷小鼠氧化应激及动脉粥样硬化斑块稳定性的影响

目的观察血管紧张素Ⅱ1型受体拮抗剂氯沙坦对载脂蛋白E基因缺陷小鼠氧化应激及主动脉粥样斑块中血管平滑肌细胞、巨噬细胞数量影响,探讨氯沙坦稳定斑块的作用及可能机制。方法27只8周龄雄性载脂蛋白E基因缺陷小鼠随机等分三组:对照组、氯沙坦低剂量组5 mg/(kg.d)]及氯沙坦高剂量组25 mg/(kg.d)],20周后处死动物。常规生物化学法测定血清一氧化氮含量、超氧化物歧化酶活性、丙二醛及血脂水平;采用HE染色法观察小鼠主动脉粥样硬化病变形成;免疫组织化学法分析粥样斑块中血管平滑肌细胞和巨噬细胞数量。结果三组间血脂水平无显著性差异;与对照组相比,氯沙坦低、高剂量组血清一氧化氮水平和超氧化物歧化酶活性均明显升高(P<0.01)、丙二醛水平显著减低(P<0.05和P<0.01),且氯沙坦低剂量和高剂量组间也有明显差异(P<0.01);氯沙坦干预后动脉粥样斑块纤维帽厚,脂质核心小;氯沙坦治疗组斑块中平滑肌细胞数量显著增加(P<0.01)、巨噬细胞数量明显降低(P<0.01),且氯沙坦高剂量组较低剂量组作用更明显(P<0.01)。结论氯沙坦在不影响血脂水平情况下,可通过减轻载脂蛋白E基因缺陷小鼠氧化应激,增加斑块中平滑肌细胞数量,降低巨噬细胞数量,可能起到稳定粥样斑块作用,且随剂量增加作用增强。

The Effects of Losartan on Oxidative Stress and Stability of Atheromatous Plaque in Apolipoprotein E Gene-Deficient Mice

Aim To investigate the effects of losartan on oxidative stress and the contents of vascular smooth muscle cells(VSMC) and macrophages in aortic atheromatous plaques of apolipoprotein E gene-deficient(Apo E~(-/-)) mice. Methods Twenty seven Apo E~(-/-) mice were randomly divided into three groups: control group,low dose losartan group5 mg/(kg·d)] and high dose losartan group25 mg/(kg·d)].The period of administration was 20 weeks.Serum nitric oxide(NO),superoxide dismutase(SOD),malondialdehyde(MDA)and serum lipids were measured by routine biochemical method.Aortic paraffin slice were prepared for histomorphological observation.The contents of VSMC and macrophages were detected by immunological histochemical method. Results There were no significant difference in serum lipids among three groups.Comparing with the control group,serum NO levels of the two treatment groups were significantly increased(p<0.01),the activity of SOD was notably enhanced(p<0.01),content of MDA was markedly decreased(p<0.05 and p<0.01).There were also significant differences between the two treatment groups(p<0.01).The atheromatous plaques of the two treatment groups contained some thick fibrous caps and little lipid cores.The contents of VSMC in the two treatment groups were significantly higher than that of control group(p<0.01).On the contrary,macrophages were notably lower than that of control group(p<0.01).Meanwhile,there were also significant differences between the two treatment groups(p<0.01 and p<0.05). Conclusions Without affecting the serum lipids,losartan can attenuate oxidative stress in Apo E~(-/-) mice and stabilize atheromatous plaque by means of increasing the content of VSMC and reducing macrophages.