葛根素诱导血管生成的作用及分子机制研究
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摘要
目的：研究葛根素诱导血管生成的作用及其分子机制。
方法：分别采用体外培养大鼠胸主动脉环模型和心肌梗死大鼠模型，应用显微镜记数的方法，测定培养大鼠胸主动脉环的血管生成情况；用TTC染色的方法测定心肌梗死面积；免疫组化的方法检测心肌微血管密度(MVD)；分光光度法检测血清NO的水平；RT-PCR的方法检测心肌HIF-1、VEGF、eNOS mRNA的表达；Western-Blot的方法检测心肌eNOS、iNOS、AKT、p-AKT蛋白表达。
结果：①葛根素有明显的抗心肌缺血的作用，60～120mg／kg葛根素腹腔注射四周能明显缩小大鼠心肌梗死面积。②葛根素能明显诱导血管生成：实验表明，6.25～100mg／mL葛根素均能促进体外培养大鼠胸主动脉环血管生成作用；120mg／kg葛根素腹腔注射四周能明显增加心肌梗死大鼠缺血心肌和非缺血心肌的微血管密度。③葛根素诱导血管生成的作用主要与其激活HIF-VEGF-AKT-eNOS-NO信号转导机制有关，主要表现在以下几个方面：a RT-PCR结果显示增加心肌梗死大鼠心肌HIF-1、VEGF、eNOS mRNA表达；b Western-Blot结果显示增加心肌梗死大鼠心肌eNOS蛋白表达和AKT磷酸化水平的蛋白表达；c 增加心肌梗死大鼠血清NO水平。
结论：葛根素在体内外试验中均有诱导血管生成作用，这可能是葛根素抗心肌缺血作用的重要机理，葛根素诱导血管生成作用的分子机制与其激活HIF-VEGF-AKT-eNOS-NO信号转导通路有关。
Objective: To investigate the effect and molecular mechanism of puerarin on angiogenesis.
Methods: Using rat aortic ring assay and rat myocardial infarction model, the growth of microvessels was observed by counting the number of newly formed microvessels using microscope. Immunohistochemistry staining was used to examine myocardial microvessel density (MVD). Spectrophotometry was used to examine serum nitric oxide levels. The gene expression of myocardial HIF-1, VEGF and eNOS was examined by RT-PCR. Westem-Blot was applied to detect the protein expression of myocardial eNOS、 iNOS、 AKT、 p-AKT.
Results: (1) Puerarin was shown to have protective effect on myocardial ischemia. Puerarin (120, 60mg/kg, i.p.) could reduce the infarct area in the heart of rat with myocardium infarction. (2) Puerarin could induce angiogenesis. Puerarin at concentrations from 6.25 to 100mg/mL could induce angiogenesis in the culture of rat aortic rings. Puerarin (120mg/kg, i.p.) induced angiogenesis in ischemic and non-ischemic myocardium of rats with myocardial infarction. (3) The effect of puerarin on angiogenesis was realized through HIF-VEGF-AKT-eNOS-NO signal pathways shown below: a) Puerarin could increase the gene expression of myocardial HIF-1, VEGF and eNOS. b) Puerarin could increase myocardial eNOS protein expression and AKT protein phosphorylation level, c) Puerarin could increase serum nitric oxide level of rat with myocardium infarction.
Conclusion: Puerarin induced angiogenesis in vitro and in vivo, which is one of the mechanisms of curing coronary artery diseases. The molecular mechanisms of puerarin on angiogenesis may be correlated with HIF-VEGF-AKT-eNOS-NO signal pathways.
方法：分别采用体外培养大鼠胸主动脉环模型和心肌梗死大鼠模型，应用显微镜记数的方法，测定培养大鼠胸主动脉环的血管生成情况；用TTC染色的方法测定心肌梗死面积；免疫组化的方法检测心肌微血管密度(MVD)；分光光度法检测血清NO的水平；RT-PCR的方法检测心肌HIF-1、VEGF、eNOS mRNA的表达；Western-Blot的方法检测心肌eNOS、iNOS、AKT、p-AKT蛋白表达。
结果：①葛根素有明显的抗心肌缺血的作用，60～120mg／kg葛根素腹腔注射四周能明显缩小大鼠心肌梗死面积。②葛根素能明显诱导血管生成：实验表明，6.25～100mg／mL葛根素均能促进体外培养大鼠胸主动脉环血管生成作用；120mg／kg葛根素腹腔注射四周能明显增加心肌梗死大鼠缺血心肌和非缺血心肌的微血管密度。③葛根素诱导血管生成的作用主要与其激活HIF-VEGF-AKT-eNOS-NO信号转导机制有关，主要表现在以下几个方面：a RT-PCR结果显示增加心肌梗死大鼠心肌HIF-1、VEGF、eNOS mRNA表达；b Western-Blot结果显示增加心肌梗死大鼠心肌eNOS蛋白表达和AKT磷酸化水平的蛋白表达；c 增加心肌梗死大鼠血清NO水平。
结论：葛根素在体内外试验中均有诱导血管生成作用，这可能是葛根素抗心肌缺血作用的重要机理，葛根素诱导血管生成作用的分子机制与其激活HIF-VEGF-AKT-eNOS-NO信号转导通路有关。
Objective: To investigate the effect and molecular mechanism of puerarin on angiogenesis.
Methods: Using rat aortic ring assay and rat myocardial infarction model, the growth of microvessels was observed by counting the number of newly formed microvessels using microscope. Immunohistochemistry staining was used to examine myocardial microvessel density (MVD). Spectrophotometry was used to examine serum nitric oxide levels. The gene expression of myocardial HIF-1, VEGF and eNOS was examined by RT-PCR. Westem-Blot was applied to detect the protein expression of myocardial eNOS、 iNOS、 AKT、 p-AKT.
Results: (1) Puerarin was shown to have protective effect on myocardial ischemia. Puerarin (120, 60mg/kg, i.p.) could reduce the infarct area in the heart of rat with myocardium infarction. (2) Puerarin could induce angiogenesis. Puerarin at concentrations from 6.25 to 100mg/mL could induce angiogenesis in the culture of rat aortic rings. Puerarin (120mg/kg, i.p.) induced angiogenesis in ischemic and non-ischemic myocardium of rats with myocardial infarction. (3) The effect of puerarin on angiogenesis was realized through HIF-VEGF-AKT-eNOS-NO signal pathways shown below: a) Puerarin could increase the gene expression of myocardial HIF-1, VEGF and eNOS. b) Puerarin could increase myocardial eNOS protein expression and AKT protein phosphorylation level, c) Puerarin could increase serum nitric oxide level of rat with myocardium infarction.
Conclusion: Puerarin induced angiogenesis in vitro and in vivo, which is one of the mechanisms of curing coronary artery diseases. The molecular mechanisms of puerarin on angiogenesis may be correlated with HIF-VEGF-AKT-eNOS-NO signal pathways.
引文
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