阿托伐他汀与一氧化碳供体分子3联用对动脉粥样硬化易损斑块模型大鼠炎症及氧化应激指标的影响

目的:研究阿托伐他汀与一氧化碳供体分子3(CORM-3)联用对动脉粥样硬化(AS)易损斑块模型大鼠炎症及氧化应激指标的影响。方法:取大鼠随机分为对照组(灌胃生理盐水)、模型组(灌胃生理盐水)、他汀组灌胃阿托伐他汀2 mg/kg]、他汀+CORM-3组灌胃阿托伐他汀2 mg/kg+腹腔注射CORM-3 10 mg/kg],每组8只。对照组大鼠予以基础饲料喂养,右颈总动脉只经历手术暴露但不予损伤并用生理盐水代替药物干预;其余3组大鼠均予以高脂饲料喂养+右颈总动脉损伤+异种蛋白注射刺激免疫炎症反应等方法复制AS易损斑块模型,继续饲养10周后,给予相应药物进行干预,每天1次,连续2周。末次给药24 h后取腹腔动脉血,使用全自动生化分析仪测定血浆中低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)浓度,采用酶联免疫吸附试验检测血浆中超敏C反应蛋白(hs-CRP)、白细胞介素10(IL-10)、单核细胞超化蛋白1(MCP-1)、基质金属蛋白酶9(MMP-9)水平,化学比色法测定血浆中丙二醛(MDA)、氧化修饰型低密度脂蛋白(ox-LDL)水平,Western blot法测定血红素氧合酶1(HO-1)蛋白表达水平,并取右颈总动脉在光镜下观察病理学变化。结果:与对照组比较,模型组大鼠LDL-C、hs-CRP、MCP-1、MMP-9、MDA、ox-LDL水平和HO-1蛋白表达水平均明显升高(P<0.05),HDL-C、IL-10水平均明显降低(P<0.05),右颈总动脉形成明显的易损斑块。与模型组比较,他汀组和他汀+CORM-3组大鼠LDL-C、hs-CRP、MCP-1、MMP-9、MDA、ox-LDL水平均明显降低(P<0.05),HDL-C、IL-10水平和HO-1蛋白表达水平均明显升高(P<0.05),其中除LDL-C、HDL-C外其余指标他汀+CORM-3组改善效果较他汀组更明显(P<0.05),他汀组颈动脉斑块改变尚不明显,但他汀+CORM-3组AS病变较模型组和他汀组显著减轻,斑块结构也更趋稳定。结论:阿托伐他汀与CORM-3联用对AS易损斑块模型大鼠炎症及氧化应激指标的改善作用强于单用阿托伐他汀,能促进AS易损斑块稳定。

Effects of Atorvastatin Combined with CORM-3 on Inflammation and Oxidative Stress Indexes in Atherosclerotic Vulnerable Plaque Model Rats

OBJECTIVE:To study the effects of atorvastatin combined with carbon monoxide releasing molecule 3(CORM-3)on inflammation and oxidative stress indexes in atherosclerotic(AS)vulnerable plaque model rats.METHODS:The rats were randomly divided into control group(normal saline,i.g.),model group(normal saline,i.g.),statin group(atorvastatin 2 mg/kg,i.g.),and statin+CORM-3 group(atorvastatin 2 mg/kg,i.g.+CORM-3 10 mg/kg,i.p.),with 8 rats in each group.Control group was fed with basal diet,and the right common carotid artery was exposed to surgery without injury and was treated with normal saline instead of drug;other three groups were fed with high-fat diet+right common carotid artery injury+heteroprotein injection to induce AS vulnerable plaque model,for 10 weeks;and then they were given relevant medicine for intervention,once a day,for consecutive 2 weeks.24 h after last medication,abdominal artery blood was collected;the concentration of LDL-C and HDL-C were determined by fully automatic biochemical analyzer.The levels of hs-CRP,IL-10,MCP-1 and MMP-9 in plasma were detected by ELISA;plasma levels of MDA and oxidized low density lipoprotein(ox-LDL)were determined by chemical colorimetry;the protein expression of heme oxygenase-1(HO-1)was determined by Western blot.The pathological changes of right common carotid artery were observed under light microscope.RESULTS:Compared with control group,the levels of LDL-C,hs-CRP,MCP-1,MMP-9,MDA and ox-LDL,and protein expression of HO-1 were increased significantly(P<0.05),while the levels of HDL-C and IL-10 were decreased significantly in model group(P<0.05);the right common carotid artery formed obvious AS plaques.Compared with model group,the levels of LDL-C,hs-CRP,MCP-1,MMP-9,MDA and ox-LDL were decreased significantly in statin group and statin+CORM-3 group in model group(P<0.05),while the levels of HDL-C,IL-10 and the protein expression of HO-1 were increased significantly(P<0.05).Except for LDL-C and HDL-C,the improvement of other indexes in statin+CORM-3 group was more significant than statin group(P<0.05);pathological changes of right common carotid artery in statin group were not obvious,but the pathological changes of rats in statin+CORM-3 group were significantly alleviated and plaque structure also tended to be more stable.CONCLUSIONS:Atorvastatin combined with CORM-3 is better than atorvastatin alone in improving inflammation and oxidative stress indexes of AS vulnerable plaque model rats,and can promote the stability of AS vulnerable plaques.