康欣胶囊对动脉粥样硬化斑块稳定性影响的临床与实验研究
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摘要
目的观察补肾健脾、养血活血的中药康欣胶囊对辨证为肾虚血瘀型颈动脉粥样硬化斑块的临床作用；研究康欣胶囊对球囊损伤建立的兔动脉粥样硬化模型颈动脉斑块的病理学改变及斑块内基质金属蛋白酶2(MMP-2)的蛋白表达、血管细胞黏附分子—1(VCAM-1)的蛋白及mRNA表达，探讨其稳定斑块的可能机制。
方法(1)将60例颈动脉粥样硬化患者，随机分为治疗组与对照组。治疗组30例给予康欣胶囊治疗(每次3粒，每日3次口服)；对照组服用阿托伐他汀钙(每次服2片，每日1次)。两组患者均连续用药12周。用高分辨率超声无创检测颈动脉粥样硬化患者颈动脉血管壁的结构、斑块的形态及血流动力学。生化仪检测总胆固醇(Tc)、甘油三脂(Tg)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、高敏C-反应蛋白(hs-CRP)及纤维蛋白原(Fib)并进行相关分析(2)用球囊牵拉法损伤颈动脉内膜，之后高胆固醇饲料喂养6周建立动脉粥样硬化模型。40只纯种雄性新(?)兰大耳白兔随机分为5组：模型组(左侧颈总动脉手术+高脂肪饮食)；阿托伐他汀钙组(左侧颈总动脉手术+高脂肪饮食+阿托伐他汀钙2.5mg／kg／d)；康欣胶囊低剂量组(左侧颈总动脉手术+高脂肪饮食+康欣胶囊0.4g／kg／d)；康欣胶囊高剂量组(左侧颈总动脉手术+高脂肪饮食+康欣胶囊1.6g／kg／d)；对照组(分离结扎左颈外动脉，不拉伤+普通饲料)。免疫组化法和免疫印迹法分别检测基质金属蛋白酶2(MMP-2)、血管细胞粘附分子-1(VCAM-1)蛋白质在动脉壁的表达，RT-PCR的方法检测各组动物动脉壁匀浆中VCAM-1mRNA的表达，在光镜下观察动脉粥样硬化血管形态学并进行斑块病理学分析。
结果1．康欣胶囊能使患者颈动脉粥样硬化软斑得以改善，斑块面积(Area)，斑块积分(Crouse)、中内膜厚度减少(IMT)，血管阻力指数减轻(RI)，降低血(?)Tc、Tg、hs-CRP及Fib。与治疗前比较有显著性差异(P＜0.05或P＜0.01)，相关分析表明hs-CRP、Fib与IMT及Area成正相关。2．康欣胶囊干预组动物血管腔壁比(W／L)、平均光密度、阳性面积百分比均较模型组小，血脂降低，动脉壁组织MMP-2及VCAM-1蛋白质含量及VCAM-1mRNA表达较模型组下调，差异有显著性(P＜0.05或P＜0.01)，以大剂量组效果为佳。
结论康欣胶囊可降低胆固醇、甘油三脂、低密度脂蛋白胆固醇及纤维蛋白原，下调MMP-2、VCAM-1、hs-CRP等炎性介质表达，提高纤维帽组织的稳定性，进而达到稳定斑块的作用。
Objectives:
Traditional Chinese medicine Kangxin capsule can tonify the kidney and the spleen andcan also nourish the blood and invigorate the circulation of blood. This paper is aimed toobserve the clinical effect of Kangxin capsule on the patients who suffer from carotidatherosclerotic plaque with kidney asthenia, blood stasis syndrome. It also uses the rabbitatherosclerosis model with the balloon-injured angioplasty to study the effect of Kangxincapsule on the pathological change of the rabbit's carotid atherosclerotic plaque and theprotein expression of matrix metalloproteinase-2 (MMP-2), the vasc(?)lar cell adhesionmolecule-1(VCAM-1) and the expression of VCAM-1mRNA in order to explore the possiblemechanism of stabilizing the atherosclerotic plaque.
Methods:
(1) Sixty carotid atherosclerosis (CAS) patients were randomly assigned into 2groups,the treatment group (30cases) with Kangxin capsule(3pills tid) and the control group(30cases) with Atorvastatin Calcium(20mg qd).Both were treated for 12weeks. To test carotidvascular structure, plaque shape and hemodynamics of the atherosclerotic patients withhigh-resolution ultrasound. To test serum cholesterol (Tc), triglyceride (Tg), high densitylipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), high-sensitiveC-reactive protein (hs-CRP) and fibrinogen (Fib) with biochemical instrument, and to carryout correlative analysis. (2) Establish the model by injuring the rabbits' carotid intima withthe balloon-injured angioplasty, followed with high cholesterol feeding for sixweeks. Randomly divided forty healthy male New Zealand white rabbits into five groups:model group, the Atorvastatin Calcium treating group, small-dose Kangxin group, large-dose Kangxin group, and control group. To test the expression of MMP-2 a d VCAM-1 in theartery with immunohistochemistry and western blot and also the expression of VCAM-1mRNA in the artery with RT-PCR, and observe the morphology of the atherosclerotic vas andmake a pathological analysis.
Results:
(1) Kangxin capsule can improve the malacoplakia of the carotid atherosclerosis,significantly decrease the Crouse of the carotid plaque, intima-mediathickness (IMT),vascular resistant index, and reduce serum Tc,Tg, LDL-C, hs-CRP, and Fib, which makes asharp contrast with those before the treatment (P＜0.05orP＜0.01). The results also suggest thaths-CRP, Fib were significantly positively correlated with IMT and Area. (2) Comparedwith the model group, the ratio of the thickness of wall to the area of lumina(W/L), averageoptical density, and the percentage of positive area of Kangxin-treated group are smaller. Thelevel of the blood lipid, the protein content of artery wall such as MMP-2 and VCAM-1 andthe expression of VCAM-1 mRNA are lowered in the Kangxin-treated group. The differencesare significant (P＜0.05or P＜0.01). The effect of large-dose Kangxin group shows synergiceffects.
Conclusion:
Kangxin capsule can reduce Tc, Tg, LDL-C, and hs-CRP, Fib, lower the expression ofmediators of inflammation such as MMP-2, VCAM-1, hs-CRP, and improve the stability offiber hat. In this way, it can stabilize the plaque.
方法(1)将60例颈动脉粥样硬化患者，随机分为治疗组与对照组。治疗组30例给予康欣胶囊治疗(每次3粒，每日3次口服)；对照组服用阿托伐他汀钙(每次服2片，每日1次)。两组患者均连续用药12周。用高分辨率超声无创检测颈动脉粥样硬化患者颈动脉血管壁的结构、斑块的形态及血流动力学。生化仪检测总胆固醇(Tc)、甘油三脂(Tg)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、高敏C-反应蛋白(hs-CRP)及纤维蛋白原(Fib)并进行相关分析(2)用球囊牵拉法损伤颈动脉内膜，之后高胆固醇饲料喂养6周建立动脉粥样硬化模型。40只纯种雄性新(?)兰大耳白兔随机分为5组：模型组(左侧颈总动脉手术+高脂肪饮食)；阿托伐他汀钙组(左侧颈总动脉手术+高脂肪饮食+阿托伐他汀钙2.5mg／kg／d)；康欣胶囊低剂量组(左侧颈总动脉手术+高脂肪饮食+康欣胶囊0.4g／kg／d)；康欣胶囊高剂量组(左侧颈总动脉手术+高脂肪饮食+康欣胶囊1.6g／kg／d)；对照组(分离结扎左颈外动脉，不拉伤+普通饲料)。免疫组化法和免疫印迹法分别检测基质金属蛋白酶2(MMP-2)、血管细胞粘附分子-1(VCAM-1)蛋白质在动脉壁的表达，RT-PCR的方法检测各组动物动脉壁匀浆中VCAM-1mRNA的表达，在光镜下观察动脉粥样硬化血管形态学并进行斑块病理学分析。
结果1．康欣胶囊能使患者颈动脉粥样硬化软斑得以改善，斑块面积(Area)，斑块积分(Crouse)、中内膜厚度减少(IMT)，血管阻力指数减轻(RI)，降低血(?)Tc、Tg、hs-CRP及Fib。与治疗前比较有显著性差异(P＜0.05或P＜0.01)，相关分析表明hs-CRP、Fib与IMT及Area成正相关。2．康欣胶囊干预组动物血管腔壁比(W／L)、平均光密度、阳性面积百分比均较模型组小，血脂降低，动脉壁组织MMP-2及VCAM-1蛋白质含量及VCAM-1mRNA表达较模型组下调，差异有显著性(P＜0.05或P＜0.01)，以大剂量组效果为佳。
结论康欣胶囊可降低胆固醇、甘油三脂、低密度脂蛋白胆固醇及纤维蛋白原，下调MMP-2、VCAM-1、hs-CRP等炎性介质表达，提高纤维帽组织的稳定性，进而达到稳定斑块的作用。
Objectives:
Traditional Chinese medicine Kangxin capsule can tonify the kidney and the spleen andcan also nourish the blood and invigorate the circulation of blood. This paper is aimed toobserve the clinical effect of Kangxin capsule on the patients who suffer from carotidatherosclerotic plaque with kidney asthenia, blood stasis syndrome. It also uses the rabbitatherosclerosis model with the balloon-injured angioplasty to study the effect of Kangxincapsule on the pathological change of the rabbit's carotid atherosclerotic plaque and theprotein expression of matrix metalloproteinase-2 (MMP-2), the vasc(?)lar cell adhesionmolecule-1(VCAM-1) and the expression of VCAM-1mRNA in order to explore the possiblemechanism of stabilizing the atherosclerotic plaque.
Methods:
(1) Sixty carotid atherosclerosis (CAS) patients were randomly assigned into 2groups,the treatment group (30cases) with Kangxin capsule(3pills tid) and the control group(30cases) with Atorvastatin Calcium(20mg qd).Both were treated for 12weeks. To test carotidvascular structure, plaque shape and hemodynamics of the atherosclerotic patients withhigh-resolution ultrasound. To test serum cholesterol (Tc), triglyceride (Tg), high densitylipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), high-sensitiveC-reactive protein (hs-CRP) and fibrinogen (Fib) with biochemical instrument, and to carryout correlative analysis. (2) Establish the model by injuring the rabbits' carotid intima withthe balloon-injured angioplasty, followed with high cholesterol feeding for sixweeks. Randomly divided forty healthy male New Zealand white rabbits into five groups:model group, the Atorvastatin Calcium treating group, small-dose Kangxin group, large-dose Kangxin group, and control group. To test the expression of MMP-2 a d VCAM-1 in theartery with immunohistochemistry and western blot and also the expression of VCAM-1mRNA in the artery with RT-PCR, and observe the morphology of the atherosclerotic vas andmake a pathological analysis.
Results:
(1) Kangxin capsule can improve the malacoplakia of the carotid atherosclerosis,significantly decrease the Crouse of the carotid plaque, intima-mediathickness (IMT),vascular resistant index, and reduce serum Tc,Tg, LDL-C, hs-CRP, and Fib, which makes asharp contrast with those before the treatment (P＜0.05orP＜0.01). The results also suggest thaths-CRP, Fib were significantly positively correlated with IMT and Area. (2) Comparedwith the model group, the ratio of the thickness of wall to the area of lumina(W/L), averageoptical density, and the percentage of positive area of Kangxin-treated group are smaller. Thelevel of the blood lipid, the protein content of artery wall such as MMP-2 and VCAM-1 andthe expression of VCAM-1 mRNA are lowered in the Kangxin-treated group. The differencesare significant (P＜0.05or P＜0.01). The effect of large-dose Kangxin group shows synergiceffects.
Conclusion:
Kangxin capsule can reduce Tc, Tg, LDL-C, and hs-CRP, Fib, lower the expression ofmediators of inflammation such as MMP-2, VCAM-1, hs-CRP, and improve the stability offiber hat. In this way, it can stabilize the plaque.
引文
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