参芪复方调控GK大鼠血管PTEN/PI3K通路与血管新生的实验研究
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摘要
目的：探讨以参芪复方为代表的2型糖尿病(T2DM)基本治法——益气养阴、活血化瘀法对GK大鼠(Goto-Kakizaki wister rates)2型糖尿病大血管病变主动脉PTEN/PI3K通路与血管新生的影响与作用机制,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：选择随机血糖≥11.1mmol/l的GK大鼠随机分为GK空白组、模型组、西药阿托伐他汀组、中药参芪复方组,另设正常Wistar对照组。模型、西药、中药组给予L-NAME 0.1mg·ml-1·d-1,加入饮用水中进行造模。正常组喂饲普通饲料,其余各组喂饲高脂饲料时间为35天。造模同时开始给予相应受试药物,周期35天。期间观察动物一般状况、饮水量、摄食量、体重、随机血糖。实验结束时,腹主动脉采血,冰上取主动脉。检测各组血糖、血脂水平,ELISA法检测血清C-反应蛋白(CRP),HE染色对腹主动脉进行形态学观察,双抗体夹心ABC-ELISA法测定主动脉血管内皮生长因子(VEGF)含量,实时荧光定量PCR技术检测主动脉PTENmRNA、PI3Kp85mRNA的表达水平,Western blot法检测主动脉PI3Kp85、Phospho-PI3Kp85、细胞间黏分子(ICAM-1)蛋白表达水平。
结果：参芪复方能显著改善GK大鼠一般状态、糖脂代谢及腹主动脉形态学变化。参芪复方组大鼠的血清CRP、主动脉ICAM-1蛋白表达及主动脉VEGF含量较模型组显著降低(P<0.05)；主动脉PTENmRNA表达较模型组显著升高(P<0.01), PI3Kp85mRNA与Phospho-PI3K p85蛋白表达较模型组均显著降低(P<0.05)。
结论：降低血清CRP含量、主动脉ICAM-1蛋白表达,减轻整体炎症状态与局部炎性浸润；降低主动脉VEGF含量,升高PTENmRNA表达水平,抑制主动脉PI3Kp85mRNA与Phospho-PI3Kp85蛋白表达,调控PTEN/PI3K信号通路,从而抑制血管新生可能是参芪复方抑制糖尿病动脉粥样硬化,防治DM大血管病变的部分作用机制。
Objective:To research the mechanisms of ShenQi prescription representing the methods of tonifying Qi and Yin and promoting blood circulation to dissipate stasis that affect PTEN/PI3K signal transduction and angiogenesis of GK rats (Goto-Kakizaki wistar rats) with T2DM Macroangiopathy.
Method:Departed GK rats (RBS≥11.1mmol/l) as GK group、model group. atorvastatin group、ShenQi prescription group and Wistar rats act as the normal group. Give high fat diet to GK rats and ordinary feed to Wistar rats. In order to build the T2DM Macroangiopathy model, admin the Nω-nitro-L-arginine methyl ester(L-NAME) 0.1 mg·ml-1·d-1 in drinking water to the model group、atorvastatin group and ShenQi prescription group. At the same time, the cure group treated by ShenQi prescription or atorvastatin for 35 days. In the experiment period, observed general status and measured the values of drinking, eating and body weight, detect the blood glucose every week. At the end, detect blood fat and CRP, detect abdominal aorta vessel wall by HE Staining; detect VEGF in thoracic aorta vessel wall by ABC-ELISA; estimated PTEN and PI3Kp85amRNA expression in abdominal aorta vessel wall by real-time PCR; estimated the PI3Kp85、Phospho-PI3K p85 and ICAM-1 protein expression in thoracic aorta vessel wall by western blot.
Result:ShenQi prescription can improve GK rats'common state, degraded the blood glucose and fat、blood secum CRP. ICAM-1 and VEGF in thoracic aorta vessel wall (P<0.05), increase the PTENmRNA expression (P<0.01), restrain the PI3Kp85mRNA expression and phospho-PI3Kp85 protein expression in abdominal aorta vessel wall (P<0.05)
Conclusion:Degraded the blood glucose and fat、blood secum CRP、ICAM-1 and VEGF in thoracic aorta vessel wall, increase the PTENmRNA expression, restrained the PI3Kp85mRNA and phospho-PI3Kp85 protein expression, regulated PTEN/PI3K cell signal maybe one of the possible curing mechanisms that inhibit angiogenesis and prevented T2DM Macroangiopathy by ShenQi prescription.
方法：选择随机血糖≥11.1mmol/l的GK大鼠随机分为GK空白组、模型组、西药阿托伐他汀组、中药参芪复方组,另设正常Wistar对照组。模型、西药、中药组给予L-NAME 0.1mg·ml-1·d-1,加入饮用水中进行造模。正常组喂饲普通饲料,其余各组喂饲高脂饲料时间为35天。造模同时开始给予相应受试药物,周期35天。期间观察动物一般状况、饮水量、摄食量、体重、随机血糖。实验结束时,腹主动脉采血,冰上取主动脉。检测各组血糖、血脂水平,ELISA法检测血清C-反应蛋白(CRP),HE染色对腹主动脉进行形态学观察,双抗体夹心ABC-ELISA法测定主动脉血管内皮生长因子(VEGF)含量,实时荧光定量PCR技术检测主动脉PTENmRNA、PI3Kp85mRNA的表达水平,Western blot法检测主动脉PI3Kp85、Phospho-PI3Kp85、细胞间黏分子(ICAM-1)蛋白表达水平。
结果：参芪复方能显著改善GK大鼠一般状态、糖脂代谢及腹主动脉形态学变化。参芪复方组大鼠的血清CRP、主动脉ICAM-1蛋白表达及主动脉VEGF含量较模型组显著降低(P<0.05)；主动脉PTENmRNA表达较模型组显著升高(P<0.01), PI3Kp85mRNA与Phospho-PI3K p85蛋白表达较模型组均显著降低(P<0.05)。
结论：降低血清CRP含量、主动脉ICAM-1蛋白表达,减轻整体炎症状态与局部炎性浸润；降低主动脉VEGF含量,升高PTENmRNA表达水平,抑制主动脉PI3Kp85mRNA与Phospho-PI3Kp85蛋白表达,调控PTEN/PI3K信号通路,从而抑制血管新生可能是参芪复方抑制糖尿病动脉粥样硬化,防治DM大血管病变的部分作用机制。
Objective:To research the mechanisms of ShenQi prescription representing the methods of tonifying Qi and Yin and promoting blood circulation to dissipate stasis that affect PTEN/PI3K signal transduction and angiogenesis of GK rats (Goto-Kakizaki wistar rats) with T2DM Macroangiopathy.
Method:Departed GK rats (RBS≥11.1mmol/l) as GK group、model group. atorvastatin group、ShenQi prescription group and Wistar rats act as the normal group. Give high fat diet to GK rats and ordinary feed to Wistar rats. In order to build the T2DM Macroangiopathy model, admin the Nω-nitro-L-arginine methyl ester(L-NAME) 0.1 mg·ml-1·d-1 in drinking water to the model group、atorvastatin group and ShenQi prescription group. At the same time, the cure group treated by ShenQi prescription or atorvastatin for 35 days. In the experiment period, observed general status and measured the values of drinking, eating and body weight, detect the blood glucose every week. At the end, detect blood fat and CRP, detect abdominal aorta vessel wall by HE Staining; detect VEGF in thoracic aorta vessel wall by ABC-ELISA; estimated PTEN and PI3Kp85amRNA expression in abdominal aorta vessel wall by real-time PCR; estimated the PI3Kp85、Phospho-PI3K p85 and ICAM-1 protein expression in thoracic aorta vessel wall by western blot.
Result:ShenQi prescription can improve GK rats'common state, degraded the blood glucose and fat、blood secum CRP. ICAM-1 and VEGF in thoracic aorta vessel wall (P<0.05), increase the PTENmRNA expression (P<0.01), restrain the PI3Kp85mRNA expression and phospho-PI3Kp85 protein expression in abdominal aorta vessel wall (P<0.05)
Conclusion:Degraded the blood glucose and fat、blood secum CRP、ICAM-1 and VEGF in thoracic aorta vessel wall, increase the PTENmRNA expression, restrained the PI3Kp85mRNA and phospho-PI3Kp85 protein expression, regulated PTEN/PI3K cell signal maybe one of the possible curing mechanisms that inhibit angiogenesis and prevented T2DM Macroangiopathy by ShenQi prescription.
引文
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