参芪复方对GK大鼠病变血管H0-1、P38MAPK及PGC-1mRNA影响的实验研究
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摘要
目的：本课题通过检测经参芪复方作用过的糖尿病大血管病变模型大鼠血清丙二醛(MDA)、过氧化氢(H2O：)的含量和血清超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活性水平,HE染色光镜下观察腹主动脉血管组织病理形态学改变,透射电镜观察腹主动脉血管组织细胞超微结构及线粒体变化,免疫组化法检测胸主动脉血管组织血红素氧合酶-1(HO-1)和P38丝裂原活化蛋白激酶(P38MAPK)蛋白表达水平,实时荧光定量PCR(RT-PCR)技术检测胸主动脉血管组织PGC-1mRNA表达水平,从整体宏观水平和组织微观结构两个角度检测参芪复方对糖尿病大血管病变模型大鼠血管组织的影响及对模型大鼠氧化/抗氧化系统的影响,探讨参芪复方防治糖尿病大血管病变的作用机制,为临床推广中医药防治糖尿病大血管并发症提供理论依据。
方法：选择随机血糖>11.0mmol/L的GK大鼠55只,随机分为GK空白组14只、模型组13只、西药阿托伐他汀组14只、中药参芪复方组14只,另设正常Wistar大鼠14只为正常对照组。模型组、西药组、中药组大鼠给予含Nw-硝基-L-精氨酸甲酯(L-NAME)饮用水和高脂饲料喂养进行造模,方法是按照0.1mg/ml的浓度将L-NAME加入饮用水中,由大鼠自由饮水,自由摄食高脂饲料,时间为35天。造模同时开始给予相应受试药物,Wistar组、GK空白组及GK模型组每只大鼠按5ml/kg/d计算剂量灌服生理盐水,1次/天；西药阿托伐他汀组每只大鼠按1.6mmg/kg/d(相当于体重为60kg成人20mg/d剂量的5倍)的计算灌服阿托伐他汀钙混悬液,1次/天；中药参芪复方组每只大鼠按1.44g/kg/d(相当于体重为60kg成人剂量的10倍)计算灌服中药混悬液,1次/天；灌药周期35天。实验过程中Wistar组大鼠喂饲普通全价饲料,其余各组喂饲高脂饲料,自由摄食,时间为35天。每周测量大鼠体重1次,以便及时调整给药剂量。期间每日观察并记录各组大鼠一般精神状况,饮水、摄食情况、活动情况,体毛色泽变化情况。实验结束后处死大鼠,股动脉采血,放免法检测各组大鼠血清丙二醛(MDA)、过氧化氢(H2O：)的含量水平和血清超氧化物歧化酶(SOD)、过氧化氢酶(CAT)水平；摘取并剥离胸及腹主动脉段,HE染色光镜下观察腹主动脉组织病理形态学变化,透射电镜观察腹主动脉组织细胞超微结构变化,免疫组化法检测胸主动脉组织HO-1和p38MAPK蛋白表达水平,实时荧光定量PCR技术检测胸主动脉组织PGC-1mRNA表达水平。
结果：中药参芪复方组大鼠一般精神状态及活动情况明显优于模型组大鼠；正常wistar组大鼠摄食量明显大于各GK组大鼠摄食量(P<0.01),实验过程中,中药组大鼠摄食量增加明显,至5周末实验结束时,中药组大鼠摄食量大于模型组大鼠摄食量,差异有统计学意义(P<0.01),其余各组大鼠在实验过程中摄食量无统计学差异(P>0.05)。wistar组大鼠饮水量明显小于GK大鼠饮水量(P<0.01),实验过程中各组大鼠饮水量均有增加,中药组和wistar组大鼠饮水量增加缓慢,模型组与空白组饮水量增速较快,西药组饮水量增长速度较模型组缓慢,至实验结束时,中药组大鼠饮水量显著低于模型组大鼠饮水量(P<0.01)。实验前,wistar大鼠体重明显大于GK大鼠体重(P<0.01),实验过程中各组大鼠体重逐渐增加,wistar组大鼠体重增速最快,模型组大鼠体重增速最慢,至实验结束中药组大鼠体重明显大于模型组大鼠体重(P<0.01)。实验结束时模型组大鼠血清MDA含量明显高于GK组及wistar组大鼠血清MDA含量(P<0.05),中药组和西药组大鼠血清MDA含量均明显低于模型组大鼠血清MDA含量(P<0.01),中药组和西药组大鼠血清MDA含量水平相比较无统计学差异(P>0.05)。模型组大鼠血清SOD水平低于GK组大鼠血清SOD水平,但差异无统计学意义(P>0.05),模型组大鼠血清SOD水平低于wistar组大鼠血清SOD水平,差异有统计学意义(P<0.01),中药组大鼠血清SOD水平明显高于模型组大鼠血清SOD水平,差异有统计学意义(P<0.01),西药组大鼠血清SOD水平明显高于模型组大鼠血清SOD水平,差异有统计学意义(P<0.05),中药组与西药组大鼠血清SOD水平相比较无统计学差异(P>0.05)。模型组大鼠血清CAT活性明显低于GK组、Wistar组大鼠血清CAT水平,差异有统计学意义(P<0.01),中药组大鼠与西药组大鼠血清CAT水平明显高于模型组大鼠血清CAT水平,差异有统计学意义(P<0.01),中药组大鼠血清CAT水平明显高于西药组大鼠血清CAT水平,差异有统计学意义(P0.05),中药组大鼠血清H20：水平含量明显低于模型组大鼠血清H2O：水平,差异有统计学意义(P<0.05),西药组大鼠血清H2O2水平含量低于模型组大鼠血清H2O2水平含量,但差异无统计学意义。模型组大鼠动脉组织HO-1蛋白表达水平明显低于GK组及Wistar组大鼠动脉组织HO-1蛋白表达水平,差异有统计学意义(P<0.01),中药组大鼠动脉组织HO-1蛋白表达水平明显高于模型组大鼠动脉组织HO-1蛋白表达水平,差异有统计学意义(P<0.01),西药组大鼠动脉组织HO-1蛋白表达水平与模型组大鼠动脉组织HO-1蛋白表达水平无统计学差异(P>0.05)。模型组大鼠动脉组织p38MAPK蛋白表达水平明显高于GK组、Wistar组大鼠动脉组织p38MAPK蛋白表达水平,差异有统计学意义(P<0.05),中药组与西药组大鼠动脉组织p38MAPK蛋白表达水平明显低于模型组大鼠动脉组织p38MAPK蛋白表达水平,差异有统计学意义(P<0.05),中药组与西药组大鼠动脉p38MAPK蛋白表达水平相比较无统计学差异(P>0.05)。模型组大鼠动脉组织PGC-1mRNA水平明显低于GK组、Wistar组大鼠动脉组织PGC-1mRNA水平,差异有统计学意义(P<0.01),中药组大鼠动脉组织PGC-1mRNA水平明显高于模型组大鼠动脉组织PGC-1mRNA水平,差异有统计学意义(P<0.01],西药组大鼠动脉组织PGC-1mRNA水平与模型组大鼠动脉组织PGC-1mRNA水平比较,无统计学差异(P>0.05)。模型组大鼠动脉病理形态学光镜下显示内膜增厚,腔内有大量泡沫细胞及纤维组织增生,有明显动脉粥样硬化改变,表明造模成功,中药组与西药组大鼠动脉组织病理改变较模型组动脉改变轻微。大鼠动脉组织透射电镜下观察,模型组大鼠血管细胞微结构与GK大鼠比较,内皮细胞结构不清晰或质膜破裂,内皮下层增厚,平滑肌细胞空泡变性,中膜胶原纤维增多,线粒体数量减少,中药组与西药组大鼠动脉内皮细胞超微结构病变较模型组轻微,线粒体结构较清晰。
结论：L-NAME配合高脂饲料喂养能复制GK大鼠为糖尿病大血管病变动物模型。参芪复方能明显改善糖尿病大血管病变模型大鼠精神状态,减轻多饮症状。参芪复方可以提高糖尿病大血管病变模型大鼠清除氧自由基能力,抑制氧化应激损伤,可以纠正氧化／抗氧化失衡状态。参芪复方可以增加糖尿病大血管病变模型大鼠血管内皮细胞线粒体合成,具有延缓和防治糖尿病大血管病变的作用。提高糖尿病大血管病变模型大鼠抗氧化酶,减少氧自由基,增加动脉组织HO-1蛋白表达水平,抑制p38MAPK蛋白激活,升高血管PGC-1mRNA水平,调控血管细胞线粒体合成和氧化应激水平,减少氧化应激损伤,可能是参芪复方防治糖尿病血管病变的作用机制。
Purpose:Through testing the level of MDA, H2O2and SOD、CAT, observing the pathological changes of abdominal aorta after HE staining, the ultra fine structure and mitochondrion of the cell of abdominal aorta under transmission electron microscope, the expression of HO-1、P38MAPK by SABC way, and the expression of PGC-1mRNA by RT-PCR way, this topic tests the effect of Shenqi Compound Recipe on vascular tissue and Oxidation and antioxidation system of Diabetic macrovascular disease model rats from overall and cell level, for dicussing the mechnism of Shenqi Compound Recipe in preventing Diabetic macrovascular disease, further providing therapy basis on TCM. preventing Diabetic macrovascular disease.
Method:The55GK rats that RBG>11.0mmol/L are randomly divided to Blank group (14)、 Model group(13)、Atorvastatin group(14)、Shenqi Compound Recipe group(14).14Normal Wistar rats are set as controll group. We manufacture model by let GK rats of Model group、Atorvastatin group、Shenqi Compound Recipe group drining water containing0.1mg/ml L-NAME.At the same time, The controll group、Blank group anc Model group are administered Physiological saline by5mg/kg. d; Atorvastatin group are administered Atorvastatin by1.6mg/kg. d(being5times dose of that of adults); the Shenqi Compound Recipe are administered Shenqi Compound Recipe suspension b、1.44g/kg. d (being10times dose of that of adults). The period is35days, and at the same time, the Wistar group are fed on common diet, the GK rats are fed or high fat diet.We measure the weight of rats once a week, record the mentality、 dringking、diet、activities、fur gloss. Then we killed the rats, measuring the level of MDA、H2O2、SOD、CAT of blood from Femoral artery by RIA way, observing pathological changes after HE staining and the changes of the ultra fine structure of abdominal aortic under transmission election microscope, the expression of HO-1、 P38MAPK by SABC way, and the expression of PGC-1mRNA by RT-PCR way.
Results:The mentalities and activities of Shenqi Compound Recipe group are better than that of model group; Wistar group eat more than GK groups(P<0.01). During experiment, the feeding amount of Shenqi Compound Recipe group is more than that of other GK groups from the5th week(P<0.01), while that of oher GK groups has little changes. The Wistar group drink less than the GK goups(P<0.01). During the experiment, the amount of the Wistar group and Shenqi Compound Recipe group drink increase less than other groups (P<0.01).The weight of all groups increase, that of the Wistar group increase more than that of others(P<0.01), While that of the model group slowest, and at the end of experiment, the weight of Shenqi Compound Recipe group more than the model group(P<0.01).The level of MDA of model group is higher than other GK groups(P<0.05), while there is no significant difference between Shenqi Compound Recipe and Atorvastatin group (P>0.05). The activity of SOD of model group is lower than other GK groups, but there is no statistical significance, that of Shenqi Compound Recipe and Atorvastatin groups higher than model group(P<0.01) while that between Shenqi Compound Recipe and Atorvastatin groups has no significant difference (P>0.05). The level of CAT is lower than other GK groups(P<0.01), that of Shenqi Compound Recipe and Atorvastatin group higher than that of model group(P<0.01), whlie that of Shenqi Compound Recipe higher than that of Atorvastatin group(P<0.05). The level of H2O2of moedl group is higher than GK groups, but there is no statistical significance between them(P>0.05), that of Shenqi Compound Recipe group lower than that of model group(P<0.05), and that of Atorvastatin group lower than that of model group, but no statistical significance(P>0.05). The expression of HO-1of model group is lower than that of GK rats(P<0.01). that of Shenqi Compound Recipe higher than that of model group(P<0.01), while there being no significant difference between the Atorvastatin group and the model group(P>0.05).The expression of p38MAPK is significant higher than that of other groups and that of Shenqi Compound Recipe and Atorvastatin group is lower than that of model group, while there is no significant difference between the two groups (P>0.05). The expression of PGC-1mRNA is lower than other GK groups, that of Shenqi Compound Recipe lower than that of model group (P<0.05), while that between Atorvastatin group and the model group not statistical significant(P>0.05). Through light microscope observation, the vascular intima of model group thicken, and thers is more foam cell and fibrous tissue hyperplasia and atherosclerotic changes. The changes of Shenqi Compound Recipe and Atorvastatin group is less than other GK groups, through electronic microscope observation, compared with GK rats, the structure of endothelial cells is unclear or the membrances rupture, subendothelial layer thickens, smooth muscle cell vacuolarly degenerate, collagen fiber membrance incraese, mitochodrion reduce, the ultrastructure lesions of arterial endothelial cell of Shenqi Compound Recipe and Atorvastatin groups is slighter and the mitochondrial structure is clear.
Conclusion:L-NAME combined with high fat diet can diabetic macroangiopathy animal model by GK rats. Shenqi Compound Recipe can improve the mentalities, relieve the symptoms of dringking more, improve the ability to clear oxygen free radicals of diabetic macrovascular rats, inhibit oxidative stress injury, can correct the oxidant/antioxidant imbalance, increase vascular endothelial cell mitochondria synthesis, retard and prevent diabetic macrovascular disease. The mechanism may be improving the antioxidant enzymes, reducing oxygen free radicals, increasing the level of HO-1, inhibitting the p38MAPK protein activation, increasing vascular PGC-1mRNA expression and mitochondrial biogenesis in vascular cells.
方法：选择随机血糖>11.0mmol/L的GK大鼠55只,随机分为GK空白组14只、模型组13只、西药阿托伐他汀组14只、中药参芪复方组14只,另设正常Wistar大鼠14只为正常对照组。模型组、西药组、中药组大鼠给予含Nw-硝基-L-精氨酸甲酯(L-NAME)饮用水和高脂饲料喂养进行造模,方法是按照0.1mg/ml的浓度将L-NAME加入饮用水中,由大鼠自由饮水,自由摄食高脂饲料,时间为35天。造模同时开始给予相应受试药物,Wistar组、GK空白组及GK模型组每只大鼠按5ml/kg/d计算剂量灌服生理盐水,1次/天；西药阿托伐他汀组每只大鼠按1.6mmg/kg/d(相当于体重为60kg成人20mg/d剂量的5倍)的计算灌服阿托伐他汀钙混悬液,1次/天；中药参芪复方组每只大鼠按1.44g/kg/d(相当于体重为60kg成人剂量的10倍)计算灌服中药混悬液,1次/天；灌药周期35天。实验过程中Wistar组大鼠喂饲普通全价饲料,其余各组喂饲高脂饲料,自由摄食,时间为35天。每周测量大鼠体重1次,以便及时调整给药剂量。期间每日观察并记录各组大鼠一般精神状况,饮水、摄食情况、活动情况,体毛色泽变化情况。实验结束后处死大鼠,股动脉采血,放免法检测各组大鼠血清丙二醛(MDA)、过氧化氢(H2O：)的含量水平和血清超氧化物歧化酶(SOD)、过氧化氢酶(CAT)水平；摘取并剥离胸及腹主动脉段,HE染色光镜下观察腹主动脉组织病理形态学变化,透射电镜观察腹主动脉组织细胞超微结构变化,免疫组化法检测胸主动脉组织HO-1和p38MAPK蛋白表达水平,实时荧光定量PCR技术检测胸主动脉组织PGC-1mRNA表达水平。
结果：中药参芪复方组大鼠一般精神状态及活动情况明显优于模型组大鼠；正常wistar组大鼠摄食量明显大于各GK组大鼠摄食量(P<0.01),实验过程中,中药组大鼠摄食量增加明显,至5周末实验结束时,中药组大鼠摄食量大于模型组大鼠摄食量,差异有统计学意义(P<0.01),其余各组大鼠在实验过程中摄食量无统计学差异(P>0.05)。wistar组大鼠饮水量明显小于GK大鼠饮水量(P<0.01),实验过程中各组大鼠饮水量均有增加,中药组和wistar组大鼠饮水量增加缓慢,模型组与空白组饮水量增速较快,西药组饮水量增长速度较模型组缓慢,至实验结束时,中药组大鼠饮水量显著低于模型组大鼠饮水量(P<0.01)。实验前,wistar大鼠体重明显大于GK大鼠体重(P<0.01),实验过程中各组大鼠体重逐渐增加,wistar组大鼠体重增速最快,模型组大鼠体重增速最慢,至实验结束中药组大鼠体重明显大于模型组大鼠体重(P<0.01)。实验结束时模型组大鼠血清MDA含量明显高于GK组及wistar组大鼠血清MDA含量(P<0.05),中药组和西药组大鼠血清MDA含量均明显低于模型组大鼠血清MDA含量(P<0.01),中药组和西药组大鼠血清MDA含量水平相比较无统计学差异(P>0.05)。模型组大鼠血清SOD水平低于GK组大鼠血清SOD水平,但差异无统计学意义(P>0.05),模型组大鼠血清SOD水平低于wistar组大鼠血清SOD水平,差异有统计学意义(P<0.01),中药组大鼠血清SOD水平明显高于模型组大鼠血清SOD水平,差异有统计学意义(P<0.01),西药组大鼠血清SOD水平明显高于模型组大鼠血清SOD水平,差异有统计学意义(P<0.05),中药组与西药组大鼠血清SOD水平相比较无统计学差异(P>0.05)。模型组大鼠血清CAT活性明显低于GK组、Wistar组大鼠血清CAT水平,差异有统计学意义(P<0.01),中药组大鼠与西药组大鼠血清CAT水平明显高于模型组大鼠血清CAT水平,差异有统计学意义(P<0.01),中药组大鼠血清CAT水平明显高于西药组大鼠血清CAT水平,差异有统计学意义(P
结论：L-NAME配合高脂饲料喂养能复制GK大鼠为糖尿病大血管病变动物模型。参芪复方能明显改善糖尿病大血管病变模型大鼠精神状态,减轻多饮症状。参芪复方可以提高糖尿病大血管病变模型大鼠清除氧自由基能力,抑制氧化应激损伤,可以纠正氧化／抗氧化失衡状态。参芪复方可以增加糖尿病大血管病变模型大鼠血管内皮细胞线粒体合成,具有延缓和防治糖尿病大血管病变的作用。提高糖尿病大血管病变模型大鼠抗氧化酶,减少氧自由基,增加动脉组织HO-1蛋白表达水平,抑制p38MAPK蛋白激活,升高血管PGC-1mRNA水平,调控血管细胞线粒体合成和氧化应激水平,减少氧化应激损伤,可能是参芪复方防治糖尿病血管病变的作用机制。
Purpose:Through testing the level of MDA, H2O2and SOD、CAT, observing the pathological changes of abdominal aorta after HE staining, the ultra fine structure and mitochondrion of the cell of abdominal aorta under transmission electron microscope, the expression of HO-1、P38MAPK by SABC way, and the expression of PGC-1mRNA by RT-PCR way, this topic tests the effect of Shenqi Compound Recipe on vascular tissue and Oxidation and antioxidation system of Diabetic macrovascular disease model rats from overall and cell level, for dicussing the mechnism of Shenqi Compound Recipe in preventing Diabetic macrovascular disease, further providing therapy basis on TCM. preventing Diabetic macrovascular disease.
Method:The55GK rats that RBG>11.0mmol/L are randomly divided to Blank group (14)、 Model group(13)、Atorvastatin group(14)、Shenqi Compound Recipe group(14).14Normal Wistar rats are set as controll group. We manufacture model by let GK rats of Model group、Atorvastatin group、Shenqi Compound Recipe group drining water containing0.1mg/ml L-NAME.At the same time, The controll group、Blank group anc Model group are administered Physiological saline by5mg/kg. d; Atorvastatin group are administered Atorvastatin by1.6mg/kg. d(being5times dose of that of adults); the Shenqi Compound Recipe are administered Shenqi Compound Recipe suspension b、1.44g/kg. d (being10times dose of that of adults). The period is35days, and at the same time, the Wistar group are fed on common diet, the GK rats are fed or high fat diet.We measure the weight of rats once a week, record the mentality、 dringking、diet、activities、fur gloss. Then we killed the rats, measuring the level of MDA、H2O2、SOD、CAT of blood from Femoral artery by RIA way, observing pathological changes after HE staining and the changes of the ultra fine structure of abdominal aortic under transmission election microscope, the expression of HO-1、 P38MAPK by SABC way, and the expression of PGC-1mRNA by RT-PCR way.
Results:The mentalities and activities of Shenqi Compound Recipe group are better than that of model group; Wistar group eat more than GK groups(P<0.01). During experiment, the feeding amount of Shenqi Compound Recipe group is more than that of other GK groups from the5th week(P<0.01), while that of oher GK groups has little changes. The Wistar group drink less than the GK goups(P<0.01). During the experiment, the amount of the Wistar group and Shenqi Compound Recipe group drink increase less than other groups (P<0.01).The weight of all groups increase, that of the Wistar group increase more than that of others(P<0.01), While that of the model group slowest, and at the end of experiment, the weight of Shenqi Compound Recipe group more than the model group(P<0.01).The level of MDA of model group is higher than other GK groups(P<0.05), while there is no significant difference between Shenqi Compound Recipe and Atorvastatin group (P>0.05). The activity of SOD of model group is lower than other GK groups, but there is no statistical significance, that of Shenqi Compound Recipe and Atorvastatin groups higher than model group(P<0.01) while that between Shenqi Compound Recipe and Atorvastatin groups has no significant difference (P>0.05). The level of CAT is lower than other GK groups(P<0.01), that of Shenqi Compound Recipe and Atorvastatin group higher than that of model group(P<0.01), whlie that of Shenqi Compound Recipe higher than that of Atorvastatin group(P<0.05). The level of H2O2of moedl group is higher than GK groups, but there is no statistical significance between them(P>0.05), that of Shenqi Compound Recipe group lower than that of model group(P<0.05), and that of Atorvastatin group lower than that of model group, but no statistical significance(P>0.05). The expression of HO-1of model group is lower than that of GK rats(P<0.01). that of Shenqi Compound Recipe higher than that of model group(P<0.01), while there being no significant difference between the Atorvastatin group and the model group(P>0.05).The expression of p38MAPK is significant higher than that of other groups and that of Shenqi Compound Recipe and Atorvastatin group is lower than that of model group, while there is no significant difference between the two groups (P>0.05). The expression of PGC-1mRNA is lower than other GK groups, that of Shenqi Compound Recipe lower than that of model group (P<0.05), while that between Atorvastatin group and the model group not statistical significant(P>0.05). Through light microscope observation, the vascular intima of model group thicken, and thers is more foam cell and fibrous tissue hyperplasia and atherosclerotic changes. The changes of Shenqi Compound Recipe and Atorvastatin group is less than other GK groups, through electronic microscope observation, compared with GK rats, the structure of endothelial cells is unclear or the membrances rupture, subendothelial layer thickens, smooth muscle cell vacuolarly degenerate, collagen fiber membrance incraese, mitochodrion reduce, the ultrastructure lesions of arterial endothelial cell of Shenqi Compound Recipe and Atorvastatin groups is slighter and the mitochondrial structure is clear.
Conclusion:L-NAME combined with high fat diet can diabetic macroangiopathy animal model by GK rats. Shenqi Compound Recipe can improve the mentalities, relieve the symptoms of dringking more, improve the ability to clear oxygen free radicals of diabetic macrovascular rats, inhibit oxidative stress injury, can correct the oxidant/antioxidant imbalance, increase vascular endothelial cell mitochondria synthesis, retard and prevent diabetic macrovascular disease. The mechanism may be improving the antioxidant enzymes, reducing oxygen free radicals, increasing the level of HO-1, inhibitting the p38MAPK protein activation, increasing vascular PGC-1mRNA expression and mitochondrial biogenesis in vascular cells.
引文
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