高同型半胱氨酸致动脉粥样硬化的机制及冠心康的干预研究
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摘要
目的：建立兔HHcy模型，观察HHcy兔血浆Hcy浓度、血脂变化，及主动脉内皮细胞中MCP-1、VCAM-1、Bcl-2、MMP-2的表达，探讨其与AS发病的关系，进而探讨中药复方冠心康对高蛋氨酸饮食所诱导的HHcy和AS病变的拮抗效应，为中药有效干预内皮功能障碍和早期粥样化病变提供实验依据。
方法：通过高蛋氨酸饮食建立兔高同型半胱氨酸血症和动脉粥样硬化模型，观察中药冠心康复方对HHcy模型兔血脂、血浆Hcy、胸主动脉内皮细胞中MCP-1、VCAM-1、Bcl-2、MMP-2表达水平的影响。实验选用雄性新西兰大白兔30只，体重分层，随机分为3组，每组10只，①正常对照组(对照组)：喂饲基础饲料(100 g／d)；②同型半胱氨酸模型组(模型组)：喂饲高蛋氨酸饲料(基础饲料中+1％蛋氨酸)100 g／d；③冠心康干预组(干预组)：喂饲高蛋氨酸饲料(100 g／d)+冠心康粉剂1.45g／(kg·d)(人剂量的10倍)。干预组冠心康粉剂用蒸馏水稀释后按2ml／kg灌胃，对照组和模型组给予等体积蒸馏水。每只动物分笼饲养，自由饮水，均喂饲8周。各组分别于第0，4，8周空腹取动脉血4ml，应用酶法在全自动生化分析仪上测定血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)水平，循环酶法检测血浆中总同型半胱氨酸的含量，8周末取血后处死动物，分离升主动脉至腹主动脉段。主动脉弓处取血管组织1 cm，先用生理盐水冲洗，后在10％的甲醛中固定2～4 h。液氮冻存待检。RT-PCR法检测动脉MCP-1mRNA的表达：免疫组化检测VCAM-1、Bcl-2、MMP-2蛋白表达及HE染色。观察主动脉病理变化。
结果：模型组，血浆中同型半胱氨酸浓度、血脂水平、主动脉MCP-1mRNA表达显著高于正常对照组(P＜0.05)，免疫组化示主动脉内皮细胞VCAM-1、MMP-2表达增强，Bcl-2表达降低；主动脉切片发现动脉内膜不连续，部分剥脱，平滑肌细胞排列疏松、紊乱，主动脉壁均见到程度不同的脂质浸润，其病变弥漫，泡沫细胞较多，可见斑块突出管腔；干预组，血浆中同型半胱氨酸含量、血脂水平显著低于对照组和模型组(P＜0.05)，主动脉MCP-1mRNA、VCAM-1、MMP-2表达显著弱于对照组和模型组(P＜0.05)，Bcl-2表达增强(P＜0.05)，主动脉病理形态学和免疫组织化学检测示病变轻于模型组。
结论：(1)HHcy可升高血中同型半胱氨酸浓度和血脂水平，促进MCP-1mRNA、VCAM-1、MMP-2的高表达，降低Bcl-2表达，促使AS斑块的形成。(2)中药冠心康复方能明显降低血浆中同型半胱氨酸含量，改善脂质代谢紊乱，减轻内膜增生程度，拮抗上述各种致AS因素，具有明显的抗AS作用。
Objective: By setting up arabbit HHcy model, to observe the Hcy density of bloodplasma, change of blood fat and the expression of MCP-1, VCAM-1, Bcl-2, MMP-2 inendotheliocyte of aorta, analyze their relationship with formation of AS, and thenanalyze the antagonistic effect of Guanxinkang(traditional Chinese medicine) for thepathological changes of HHcy and AS induced by homomethionin diet, so as to provideexperimental numerical data for the effectiveness of traditional Chinese medicineto interfere in functional impairment of endothelial tissue and athero- pathologicalchanges in earlier period.
Method: By setting up a rabbit HHcy and AS model induced by homomethionin diet,to observe the influence of Guanxinkang(traditional Chinese medicine) on the levelof blood fat, tHcy in blood plasma and the expression of MCP-1,VCAM-1, Bcl-2,MMP-2in endotheliocyte of aorta in model rabbit with HHcy. 30 masculine Zelanian albinorabbit have been selected for the experiment. The albino rabbit were divided intothree groups randomly, each of which was t0. The three groups include: 1) normalcontrol group(control group): fed by elementary animal feeds(100 g/d); 2) homocysteicacid model group(model group): fed by homomethionin animal feeds(adding 1% methionineinto elementary animal feeds); 3) Guanxinkang intervention group(interventiongroup): fed by homomethionin animal feeds(100 g/d) and Guanxinkang powder 1.45g/(kg·d)(as 10 times of dosage of human being). Guanxinkang powder used byintervention group are diluted by distilled water then intragastric administrationby 2 ml/kg. Identical volume distilled water are fed to control group and model group.Each rabbit is fed in different cage; water is fed freely and all are fed for 8 weeks.Each group is taken suctionarterial blood for 4ml on an empty stomach in the 0, 4th,8th week respectively, then to test the serum total cholesterol (TC)、triglycerideTG)、low density lipoprotein cholesterol (LDL-C)and high-density lipoproteincholesterol (HDL-C) by enzymic method using automatic biochemistry analyzer, and totest the contents of homocysteic acid in blood plasma by cyclophorase method. At theend of the 8th week, blood is taken and the animal is put to death, and split ascendingaorta to abdominal aorta. Then to take vascular tissue 1 cm in arcus aortae, firstlywashed by normal saline, then fix it for 2～4 hours in 10% formaldehyde and keepedfreezing by liquid nitrogen for further test. To test the expression of aortaMCP-1mRNA by RT-PCR method; and test albumen expression of VCAM-1, Bcl-2, MMP-2and HE dyeing by immunohistochemistry. To observe the pathological change of aorta.
Results: The tHey and blood fat level in blood plasma and expression of MCP-1mRNAof aorta on model group is obviously higher than that of control group (P＜0.05);the result of immunohistochemistry shows that the expression of VCAM-1 and MMP-2enhanced, Bcl-2 is lower; aorta slice shows endarterium discontinuation, strippingpartly, smooth muscle cell arrange puffly and chaotic, infiltration of lipoid ofdifferent degree are observed in aorta wall, pathological changes suffusion, morexanthoma cell, plaque protrude lumens. The they and blood fat level in blood plasmaand expression of MCP-lmRNA, VCAM-1, MMP-2 of aorta on intervention group aremuch lower than that of model group (P＜0.05); Bcl-2 of intervention group isstrengthened, and the pathomorphology and immunohistochemistry of aorta showpathological changes are slighter than model group.
Conclusion: 1) HHcy may increase the level of homocysteic acid in the blood andresults in the formulation of AS plaque and higher expression of MCP-1mRNA,VCAM-1, MMP-2 but lower expression of Bcl-2. 2) Guanxinkang may decrease the the levelof homocysteic acid in the blood, improve the metabolic disturbance of lipoids,alleviate the hyperplasy of endangium, antagonize various factor cause AS and hasevident role in anti-AS.
方法：通过高蛋氨酸饮食建立兔高同型半胱氨酸血症和动脉粥样硬化模型，观察中药冠心康复方对HHcy模型兔血脂、血浆Hcy、胸主动脉内皮细胞中MCP-1、VCAM-1、Bcl-2、MMP-2表达水平的影响。实验选用雄性新西兰大白兔30只，体重分层，随机分为3组，每组10只，①正常对照组(对照组)：喂饲基础饲料(100 g／d)；②同型半胱氨酸模型组(模型组)：喂饲高蛋氨酸饲料(基础饲料中+1％蛋氨酸)100 g／d；③冠心康干预组(干预组)：喂饲高蛋氨酸饲料(100 g／d)+冠心康粉剂1.45g／(kg·d)(人剂量的10倍)。干预组冠心康粉剂用蒸馏水稀释后按2ml／kg灌胃，对照组和模型组给予等体积蒸馏水。每只动物分笼饲养，自由饮水，均喂饲8周。各组分别于第0，4，8周空腹取动脉血4ml，应用酶法在全自动生化分析仪上测定血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)水平，循环酶法检测血浆中总同型半胱氨酸的含量，8周末取血后处死动物，分离升主动脉至腹主动脉段。主动脉弓处取血管组织1 cm，先用生理盐水冲洗，后在10％的甲醛中固定2～4 h。液氮冻存待检。RT-PCR法检测动脉MCP-1mRNA的表达：免疫组化检测VCAM-1、Bcl-2、MMP-2蛋白表达及HE染色。观察主动脉病理变化。
结果：模型组，血浆中同型半胱氨酸浓度、血脂水平、主动脉MCP-1mRNA表达显著高于正常对照组(P＜0.05)，免疫组化示主动脉内皮细胞VCAM-1、MMP-2表达增强，Bcl-2表达降低；主动脉切片发现动脉内膜不连续，部分剥脱，平滑肌细胞排列疏松、紊乱，主动脉壁均见到程度不同的脂质浸润，其病变弥漫，泡沫细胞较多，可见斑块突出管腔；干预组，血浆中同型半胱氨酸含量、血脂水平显著低于对照组和模型组(P＜0.05)，主动脉MCP-1mRNA、VCAM-1、MMP-2表达显著弱于对照组和模型组(P＜0.05)，Bcl-2表达增强(P＜0.05)，主动脉病理形态学和免疫组织化学检测示病变轻于模型组。
结论：(1)HHcy可升高血中同型半胱氨酸浓度和血脂水平，促进MCP-1mRNA、VCAM-1、MMP-2的高表达，降低Bcl-2表达，促使AS斑块的形成。(2)中药冠心康复方能明显降低血浆中同型半胱氨酸含量，改善脂质代谢紊乱，减轻内膜增生程度，拮抗上述各种致AS因素，具有明显的抗AS作用。
Objective: By setting up arabbit HHcy model, to observe the Hcy density of bloodplasma, change of blood fat and the expression of MCP-1, VCAM-1, Bcl-2, MMP-2 inendotheliocyte of aorta, analyze their relationship with formation of AS, and thenanalyze the antagonistic effect of Guanxinkang(traditional Chinese medicine) for thepathological changes of HHcy and AS induced by homomethionin diet, so as to provideexperimental numerical data for the effectiveness of traditional Chinese medicineto interfere in functional impairment of endothelial tissue and athero- pathologicalchanges in earlier period.
Method: By setting up a rabbit HHcy and AS model induced by homomethionin diet,to observe the influence of Guanxinkang(traditional Chinese medicine) on the levelof blood fat, tHcy in blood plasma and the expression of MCP-1,VCAM-1, Bcl-2,MMP-2in endotheliocyte of aorta in model rabbit with HHcy. 30 masculine Zelanian albinorabbit have been selected for the experiment. The albino rabbit were divided intothree groups randomly, each of which was t0. The three groups include: 1) normalcontrol group(control group): fed by elementary animal feeds(100 g/d); 2) homocysteicacid model group(model group): fed by homomethionin animal feeds(adding 1% methionineinto elementary animal feeds); 3) Guanxinkang intervention group(interventiongroup): fed by homomethionin animal feeds(100 g/d) and Guanxinkang powder 1.45g/(kg·d)(as 10 times of dosage of human being). Guanxinkang powder used byintervention group are diluted by distilled water then intragastric administrationby 2 ml/kg. Identical volume distilled water are fed to control group and model group.Each rabbit is fed in different cage; water is fed freely and all are fed for 8 weeks.Each group is taken suctionarterial blood for 4ml on an empty stomach in the 0, 4th,8th week respectively, then to test the serum total cholesterol (TC)、triglycerideTG)、low density lipoprotein cholesterol (LDL-C)and high-density lipoproteincholesterol (HDL-C) by enzymic method using automatic biochemistry analyzer, and totest the contents of homocysteic acid in blood plasma by cyclophorase method. At theend of the 8th week, blood is taken and the animal is put to death, and split ascendingaorta to abdominal aorta. Then to take vascular tissue 1 cm in arcus aortae, firstlywashed by normal saline, then fix it for 2～4 hours in 10% formaldehyde and keepedfreezing by liquid nitrogen for further test. To test the expression of aortaMCP-1mRNA by RT-PCR method; and test albumen expression of VCAM-1, Bcl-2, MMP-2and HE dyeing by immunohistochemistry. To observe the pathological change of aorta.
Results: The tHey and blood fat level in blood plasma and expression of MCP-1mRNAof aorta on model group is obviously higher than that of control group (P＜0.05);the result of immunohistochemistry shows that the expression of VCAM-1 and MMP-2enhanced, Bcl-2 is lower; aorta slice shows endarterium discontinuation, strippingpartly, smooth muscle cell arrange puffly and chaotic, infiltration of lipoid ofdifferent degree are observed in aorta wall, pathological changes suffusion, morexanthoma cell, plaque protrude lumens. The they and blood fat level in blood plasmaand expression of MCP-lmRNA, VCAM-1, MMP-2 of aorta on intervention group aremuch lower than that of model group (P＜0.05); Bcl-2 of intervention group isstrengthened, and the pathomorphology and immunohistochemistry of aorta showpathological changes are slighter than model group.
Conclusion: 1) HHcy may increase the level of homocysteic acid in the blood andresults in the formulation of AS plaque and higher expression of MCP-1mRNA,VCAM-1, MMP-2 but lower expression of Bcl-2. 2) Guanxinkang may decrease the the levelof homocysteic acid in the blood, improve the metabolic disturbance of lipoids,alleviate the hyperplasy of endangium, antagonize various factor cause AS and hasevident role in anti-AS.
引文
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