小檗碱联合辛伐他汀对动脉粥样硬化模型大鼠的抗动脉粥样硬化作用及其机制

目的：探讨小檗碱联合辛伐他汀对动脉粥样硬化（AS）模型大鼠胸主动脉组织中血管内皮生长因子（VEGF）、转化生长因子β1（TGF-β1）、白细胞介素18（IL-18）和白细胞介素10（IL-10）表达的影响，阐明小檗碱联合辛伐他汀抗动脉硬化的作用机制。方法：48只大鼠随机分为对照组，模型组，辛伐他汀组，低、中和高剂量小檗碱联合辛伐他汀组，每组8只。给药4周后取大鼠血清和胸主动脉组织，HE染色法观察各组大鼠胸主动脉组织病理形态表现，双抗体夹心ABC-ELISA法检测各组大鼠血清中VEGF、TGF-β1、IL-18和IL-10水平，全自动生物化学分析仪测定各组大鼠血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL-C）和高密度脂蛋白（HDL-C）水平，免疫组织化学法检测各组大鼠胸主动脉组织中VEGF、TGF-β1、IL-18和IL-10蛋白表达水平。结果：HE染色，与对照组比较，模型组大鼠主动脉内膜明显增厚、细胞内外有脂质沉积，内膜下可见坏死物沉积，内壁出现斑块、不平整，血管腔狭窄；与模型组比较，高剂量小檗碱联合辛伐他汀组大鼠动脉血管壁无明显斑块出现，内膜增厚不平整明显改善。与模型组比较，辛伐他汀组和不同剂量小檗碱联合辛伐他汀组大鼠血清中TC、TG和LDL-C水平明显降低（P<0.05或P<0.01），HDL-C水平明显升高（P<0.05）。ABC-ELISA法检测，与模型组比较，辛伐他汀组和不同剂量小檗碱联合辛伐他汀组大鼠血清中VEGF和IL-18水平均降低（P<0.05或P<0.01），TGF-β1和IL-10水平升高（P<0.05）。免疫组织化学法检测，与模型组比较，辛伐他汀组大鼠胸主动脉组织中IL-18蛋白表达水平明显降低（P<0.05），TGF-β1蛋白表达水平明显升高（P<0.05）；不同剂量小檗碱联合辛伐他汀组大鼠胸主动脉组织中VEGF和IL-18蛋白表达水平均明显降低（P<0.05），TGF-β1和IL-10蛋白表达水平明显升高（P<0.05）。结论：小檗碱联合辛伐他汀能通过下调小鼠血清和胸主动脉组织中VEGF和IL-18蛋白表达水平，上调TGF-β1和IL-10蛋白表达水平，发挥抗AS作用。

Anti-atherosclerosis effect of berberine combined with simvastatin in atherosclerosis model rats and its mechanism

Objective:To investigate the effects of berberine combined with simvastatin on the expressions of vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), interleukin-18 (IL-18) and interleukin-10 (IL-10) in the thoracic aorta tissue of the atherosclerosis (AS)model rats, and to elucidate the mechanism of anti-atherosclerosis of berberine combined with simvastatin. Methods:A total of 48 rats were divided into control group, model group, simvastatin group, low, middle and high doses of berberines combined with simvastatin groups(n=8).The serum and thoracic aorta tissue of the rats were obtained 4 weeks after adminstration. HE staining was used to observe the pathomorphology of the thoracic aorta of the rats in various goups; ABC-double antibody sandwich ELISA method was used to detect the serum VEGF, TGF-β1, IL-18 and IL-10 of the rats in various groups; automatic biochemistry analyzer was performed to determine the levels of serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterin (LDL-C), high density lipoprotein cholesterin (HDL-C) of the rats in various groups. The expression levels of VEGF, TGF-β1, IL-18, and IL-10 proteins in the aortic tissue of the rats in various groups were determined by immunohistochemistry. Results:The HE results showed that compared with control group, the intima of aorta of the rats in model group was significantly thickened, lipid deposition was observed inside and outside the cells, necrosis was observed under the intima, plaques and irregularities were observed in the inner wall, and the vascular cavity was narrowed;compared with model group, in high dose of berberine combined with simvastatin group, there was no obvious plaque on the arterial wall, and the intimal thickening was significantly improved. Compared with model group, the serum TC, TG, and LDL-C levels of the rats in simvastatin group and different doses of berberine combined with simvastatin group were significantly decreased (P< 0.05 or P< 0.01), and the serum HDL-C level was significantly increased (P< 0.05). The results of ABC-ELISA showed that compared with model group, the serum VEGF and IL-18 levels in simvastatin and different doses of berberine combined with simvastatin groups were significantly decreased (P<0.05 or P<0.01),and the serum TGF-β1 and IL-10 levels were significantly increased (P<0.05). The results of immunohistochemistry showed that compared with model group,the expression level of IL-18 protein in thoracic aorta tissue of the rats in simvastatin group was significantly decreased(P<0.05),and the expression level of TGF-β1 protein was significantly increased(P<0.05); the expression levels of VEGF and IL-18 proteins in the thoracic aorta tissue of the rats in different doses of berberine combined with simvastatin groups were significantly reduced (P<0.05),and the expression levels of TGF-β1 and IL-10 proteins were significantly increased (P<0.05). Conclusion:Berberine combined with simvastatin could control AS via the up-regulation of the expression levels of VEGF and IL-18 proteins and the down-regulation of the expression levels of TGF-β1 and IL-10 proteins in serum and thoracic aorta tissue of rats.