参芪复方对GK大鼠大血管病变氧化应激及关键抗氧化酶影响的实验研究
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摘要
目的：通过观察具有益气养阴、活血化瘀功效的参芪复方对糖尿病大血管病变GK大鼠抗氧化酶活性及血管内皮ROS重要来源——NADPH氧化酶相关亚基表达的影响,从氧化应激的角度探讨参芪复方防治糖尿病大血管病变的可能作用机制,为临床推广应用中医药防治糖尿病大血管病变提供理论依据。
方法：55只随机血糖≥)11.1mmol·L-1的5月龄雄性GK大鼠随机分成4组：GK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,另设随机血糖≤6.7mmol·L-1的5月龄雄性Wistar大鼠14只作为正常对照组。其中模型组、西药组及中药组予以一氧化氮合成酶(eNOS)抑制剂(L-NAME)0.1mg·ml-1·d-1加入饮用水中进行造模,连续造模35天。正常组喂饲普通饲料,各实验组GK大鼠喂饲高脂饲料。造模同时开始给予相应药物治疗,正常组、GK组、模型组均按5ml·kg-1·d-1灌服生理盐水,西药组按1.6mg·kg-1·d-1灌服阿托伐他汀钙悬液,中药组按1.44g·kg-1·d-1灌服参芪复方混悬液。实验期间观察动物一般状况、饮水量、摄食量,每周定时测量体重、随机血糖一次。实验35天后处死大鼠,检测各组空腹血糖水平,黄嘌呤氧化酶法测定血清超氧化物歧化酶(SOD)活性,双抗体夹心ELISA测定血清谷胱甘肽过氧化物酶(GSH-Px)、总抗氧化能力(T-AOC),硫代巴比妥酸法测定血清丙二醛(MDA)含量,荧光法测定红细胞醛糖还原酶(AR)活性,HE染色对腹主动脉进行形态学观察,利用实时荧光定量PCR技术检测胸主动脉NADPH氧化酶亚基p22phox和p47phox的mRNA表达水平。
结果：参芪复方组一般状况优于模型组,饮水量较模型组减少,体重较模型组增加,空腹血糖较模型组降低。参芪复方组大鼠血清抗氧化酶SOD、GSH-Px活性以及总抗氧化能力T-AOC较模型组升高(P<0.01),而血清MDA水平下降明显(P<0.01),红细胞AR的活性较模型组降低(P<0.01),胸主动脉p22phox mRNA、 p47phox mRNA的表达较模型组低(P<0.01)。
结论：参芪复方可以改善糖尿病大血管病变GK大鼠的一般状态,减少模型大鼠的饮水量,增加模型大鼠体重,改善糖代谢紊乱,减轻模型大鼠机体氧化应激损伤,延缓糖尿病动脉硬化的进展。其作用机理可能是通过提高模型大鼠主要抗氧化酶SOD、GSH-Px活性、抑制脂质过氧化产物的形成、提高模型大鼠总抗氧化能力,增强机体清除自由基的能力,同时抑制多元醇通路关键限速酶AR的活性,降低NADPH氧化酶亚基p22phox、p47phox在胸主动脉的表达,从源头上减少血管内皮ROS的产生,减轻主动脉氧化应激损伤等途径来实现的。
Objective:To research the effect of ShenQi prescription, which has the function of tonifying Qi and Yin and promoting blood circulation, on the oxidative stress and the expression of key enzymes in GK rats (Goto-Kakizaki wistar rats) with T2DM Macroangiopathy, and to find out the possible pathway.
Methods:Departed55GK male rats (RBS≥11.lmmol·L-1) as GK group (14rats, drenched normal saline5ml·kg-1·d-1), model group (13rats, drenched normal saline5ml·kg-1·d-1), atorvastatin group (14rats, drenched atorvastatin calcium suspension1.6mg·kg-1·d-1), ShenQi prescription group (14rats, drenched ShenQi compound recipe suspl1.44g·kg-1·d-1) and14Wistar rats act(RBS≤6.7mmol·L-1) as the normal group (drenched normal saline5ml·kg-1·d-1). GK rats were fed with high fat diet, while Wistar rats with general diet. The Nco-nitro-L-arginine methyl ester (L-NAME)0.1mg.ml-1.d-1was added into the drinking water for model, atorvastatin and ShenQi group to build the diabetes mellitus macroangiopathy model. Treating while setting up model. The experiment required35days. In the experiment period, general status were observed as well as the amount of water drinking, food intake, blood dlucose and body weight. At the end, detect the SOD by Xanthine oxidase, detect the GSH-Px and T-AOC by ABC-ELISA, detect the MDA by TBA, detect the erythrocyte AR by Fluorescence Method, estimated the mRNA expression of p22phox and p47phox in thoracic aorta vessel wall by real-time PCR, detect abdominal aorta vessel wall by HE Staining.
Results:ShenQi prescription can improve GK rats" common state. The ShenQi group had significantly higher SOD, GSH-Px and TAOC activity in blood serum compared with model group(P<0.01or P<0.05). ShenQi prescription can decrease the activity of erythrocyte AR(P<0.01), restrain the mRNA expression of p22phox mRNA and p47phox mRNA in thoracic aorta vessel wall (P<0.01).
Conclusion:Improved the activities of antioxidant enzymes (including SOD and GSH-Px), increase the Total antioxidant capacity (T-AOC)decrease the activity of erythrocyte AR, significantly downregulated the mRNA expression of p22phox and p22phox in thoracic aorta vessel wall maybe one of the possible curing mechanisms that inhibit the oxidative stress and prevented T2DM Macroangiopathy by ShenQi prescription.
方法：55只随机血糖≥)11.1mmol·L-1的5月龄雄性GK大鼠随机分成4组：GK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,另设随机血糖≤6.7mmol·L-1的5月龄雄性Wistar大鼠14只作为正常对照组。其中模型组、西药组及中药组予以一氧化氮合成酶(eNOS)抑制剂(L-NAME)0.1mg·ml-1·d-1加入饮用水中进行造模,连续造模35天。正常组喂饲普通饲料,各实验组GK大鼠喂饲高脂饲料。造模同时开始给予相应药物治疗,正常组、GK组、模型组均按5ml·kg-1·d-1灌服生理盐水,西药组按1.6mg·kg-1·d-1灌服阿托伐他汀钙悬液,中药组按1.44g·kg-1·d-1灌服参芪复方混悬液。实验期间观察动物一般状况、饮水量、摄食量,每周定时测量体重、随机血糖一次。实验35天后处死大鼠,检测各组空腹血糖水平,黄嘌呤氧化酶法测定血清超氧化物歧化酶(SOD)活性,双抗体夹心ELISA测定血清谷胱甘肽过氧化物酶(GSH-Px)、总抗氧化能力(T-AOC),硫代巴比妥酸法测定血清丙二醛(MDA)含量,荧光法测定红细胞醛糖还原酶(AR)活性,HE染色对腹主动脉进行形态学观察,利用实时荧光定量PCR技术检测胸主动脉NADPH氧化酶亚基p22phox和p47phox的mRNA表达水平。
结果：参芪复方组一般状况优于模型组,饮水量较模型组减少,体重较模型组增加,空腹血糖较模型组降低。参芪复方组大鼠血清抗氧化酶SOD、GSH-Px活性以及总抗氧化能力T-AOC较模型组升高(P<0.01),而血清MDA水平下降明显(P<0.01),红细胞AR的活性较模型组降低(P<0.01),胸主动脉p22phox mRNA、 p47phox mRNA的表达较模型组低(P<0.01)。
结论：参芪复方可以改善糖尿病大血管病变GK大鼠的一般状态,减少模型大鼠的饮水量,增加模型大鼠体重,改善糖代谢紊乱,减轻模型大鼠机体氧化应激损伤,延缓糖尿病动脉硬化的进展。其作用机理可能是通过提高模型大鼠主要抗氧化酶SOD、GSH-Px活性、抑制脂质过氧化产物的形成、提高模型大鼠总抗氧化能力,增强机体清除自由基的能力,同时抑制多元醇通路关键限速酶AR的活性,降低NADPH氧化酶亚基p22phox、p47phox在胸主动脉的表达,从源头上减少血管内皮ROS的产生,减轻主动脉氧化应激损伤等途径来实现的。
Objective:To research the effect of ShenQi prescription, which has the function of tonifying Qi and Yin and promoting blood circulation, on the oxidative stress and the expression of key enzymes in GK rats (Goto-Kakizaki wistar rats) with T2DM Macroangiopathy, and to find out the possible pathway.
Methods:Departed55GK male rats (RBS≥11.lmmol·L-1) as GK group (14rats, drenched normal saline5ml·kg-1·d-1), model group (13rats, drenched normal saline5ml·kg-1·d-1), atorvastatin group (14rats, drenched atorvastatin calcium suspension1.6mg·kg-1·d-1), ShenQi prescription group (14rats, drenched ShenQi compound recipe suspl1.44g·kg-1·d-1) and14Wistar rats act(RBS≤6.7mmol·L-1) as the normal group (drenched normal saline5ml·kg-1·d-1). GK rats were fed with high fat diet, while Wistar rats with general diet. The Nco-nitro-L-arginine methyl ester (L-NAME)0.1mg.ml-1.d-1was added into the drinking water for model, atorvastatin and ShenQi group to build the diabetes mellitus macroangiopathy model. Treating while setting up model. The experiment required35days. In the experiment period, general status were observed as well as the amount of water drinking, food intake, blood dlucose and body weight. At the end, detect the SOD by Xanthine oxidase, detect the GSH-Px and T-AOC by ABC-ELISA, detect the MDA by TBA, detect the erythrocyte AR by Fluorescence Method, estimated the mRNA expression of p22phox and p47phox in thoracic aorta vessel wall by real-time PCR, detect abdominal aorta vessel wall by HE Staining.
Results:ShenQi prescription can improve GK rats" common state. The ShenQi group had significantly higher SOD, GSH-Px and TAOC activity in blood serum compared with model group(P<0.01or P<0.05). ShenQi prescription can decrease the activity of erythrocyte AR(P<0.01), restrain the mRNA expression of p22phox mRNA and p47phox mRNA in thoracic aorta vessel wall (P<0.01).
Conclusion:Improved the activities of antioxidant enzymes (including SOD and GSH-Px), increase the Total antioxidant capacity (T-AOC)decrease the activity of erythrocyte AR, significantly downregulated the mRNA expression of p22phox and p22phox in thoracic aorta vessel wall maybe one of the possible curing mechanisms that inhibit the oxidative stress and prevented T2DM Macroangiopathy by ShenQi prescription.
引文
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