瑞舒伐他汀联合普罗布考对大鼠动脉粥样硬化炎症与氧化应激的干预效果

Intervention effects of rosuvastatin combining probucol on inflammation and oxidative stress in rats with atherosclerosis

目的观察瑞舒伐他汀联合普罗布考对大鼠动脉粥样硬化炎症及氧化应激相关指标的干预效果。方法雄性Wistar大鼠54只随机分5组,正常组(A组,n=12)、模型组(B组,n=12)、瑞舒伐他汀组(C组,n=10)、普罗布考组(D组,n=10)、瑞舒伐他汀加普罗布考组(E组,n=10)。A组普通饲料喂养,B组及药物干预组高脂饲料喂养同时给予卵清白蛋白(2.5 mg/kg)腹腔注射(5次/周)。从第9周开始,C、D、E组给予药物干预,C组给予瑞舒伐他汀5 mg/kg.d灌胃,D组给予普罗布考500 mg/kg.d灌胃,E组给予瑞舒伐他汀5 mg/kg.d+普罗布考500 mg/kg.d灌胃,A、B组给予生理盐水灌胃作为对照,连续干预8周。第16周末,所有大鼠称重,麻醉,开胸经右心房取血,留取血清。随后用ELISA法检测血清炎症指标血管内皮细胞钙黏蛋白(VE-cadherin)、脂联素(APN)及氧化应激指标8-异前列腺素-F2a(8-iso-PGF2a)、超氧化物歧化酶(SOD)表达水平。同时留取主动脉,进行HE染色,观察主动脉病理组织学变化。结果与正常组比较,模型组和药物干预组血清VE-cadherin、8-iso-PGF2a水平显著升高(P<0.01),APN、SOD水平显著降低(P<0.01),血管内膜增厚(P<0.05),内皮细胞排列紊乱,可见泡沫细胞和单核细胞,且细胞间隙增宽。与B组比较,C、D、E组血清VE-cadherin、8-iso-PGF2a水平明显降低(P<0.01),APN、SOD表达升高(P<0.05),血管壁内膜厚度变薄(P<0.01)。与C组比较,D、E组血清8-iso-PGF2a水平下降(P<0.01),SOD水平升高(P<0.01);与C组比较,E组血清VE-cadherin降低(P<0.01),APN升高(P<0.01)。与D组比较,E组血清VE-cadherin降低(P<0.05),APN升高(P<0.05);与C、D组比较,E组血管内膜变薄(P<0.05)。结论瑞舒伐他汀与普罗布考均具有抗炎和抗氧化作用,普罗布考的抗氧化作用优于瑞舒伐他汀,两药联合应用可明显降低血清VE-cadherin的表达,并提高APN的表达,减轻主动脉血管内膜的损伤,改善动脉粥样硬化。

Objective To observe the intervention effects of rosuvastatin combining probucol on inflammation and oxidative stress indexes in rats with atherosclerosis. Methods Female Wistar rats （n=54） were randomly divided into normal group （group A, n=12）, model group （group B, n=12）, rosuvastatin group （group C, n=10）, probucol group （group D, n=10） and rosuvastatin combining probucol group （group E, n=10）. Group A was given normal fodder, and group B and all drug groups were given high-fat fodder and intraperitoneal injection of egg albumin （2.5 mg/kg, 5 times a week）. From the 9th w, group C was orally given rosuvastatin （5 mg/kg.d）, group D, probucol （500 mg/kg.d）, and group E, rosuvastatin combining probucol （5 mg/kg.d＋500 mg/kg.d） for 8 w. Group A and group B were given normal saline water as control for 8 w. The expressions of serum VE-cadherin, APN, 8-iso-PGF2a and SOD were detected by using ELISA, and the histopathological changes of aorta were observed after HE staining. Results The levels of VE-cadherin and 8-iso-PGF2a increased significantly （P〈0.01）, levels of APN and SOD decreased significantly （P〈0.01）, vascular intima was thicker （P〈0.05）, the arrangement of endothelial cells was in disorder, foam cells and mononuclear cells were observed and intercellular space was broadened in groups B, C, D and E compared with group A. The levels of VE-cadherin and 8-iso-PGF2a decreased significantly （P〈0.01）, levels of APN and SOD increased （P〈0.05）, vascular intima was thinner （P〈0.01） in groups C, D and E compared with group B. The level of serum 8-iso-PGF2a decreased （P〈0.01）, level of SOD increased （P〈0.01） in groups D and E compared with group C. The level of VE-cadherin decreased （P〈0.01） and level of APN increased （P〈0.01） in group E compared with group C. The level of VE-cadherin decreased （P〈0.05） and level of APN increased （P〈0.05） in group E compared with group D. The vascular intima was thinner （P〈0.05） in group E compared with groups C and D. Conclusion Both rosuvastatin and probucol have anti-infection and anti-oxidation effects, while probucol is superior to rosuvastatin in antioxidation. The combination of these two drugs can significantly decrease the expression of serum VE-cadherin, increase APN expression, and relieve the damage of vascular intima and atherosclerosis.