参芪复方对KKAy小鼠糖尿病大血管病变差异基因表达影响的实验研究
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摘要
目的：本研究通过观察具有养阴益气、活血化瘀功效的参芪复方对糖尿病大血管病变KKAy小鼠的主动脉病理形态的影响,并应用基因芯片技术寻找参芪复方防治糖尿病大血管病变的分子靶点,探讨参芪复方防治糖尿病大血管病变的生物学作用及其机理,为中药防治糖尿病大血管病变提供分子理论依据。
方法：66只随机血糖2次≥13.9mmol·L-1的18-20周龄雄性KKAy小鼠随机分成4组：KKAy组(n=15)；糖尿病大血管病变模型组(简称模型组,n=15)；参芪复方组(n=15)；罗格列酮组(n=15)。正常C57BL/6J小鼠(n=15)做对照组。其中模型组、参芪复方组及罗格列酮组予以一氧化氮合成酶(eNOS)抑制剂(L-NAME)0.2mg-ml-1·d-1加入饮用水中进行造模,连续造模8周。正常组喂普通饲料,各实验组KKAy小鼠喂高脂饲料。造模同时给予药物治疗,正常组、KKAy组、模型组均按10ml·kg-1·d-1灌服生理盐水,中药组按14.4g·kg-1·d-1灌服参芪复方浸膏,罗格列酮组按1.33mg·kg-l·d-1灌服罗格列酮悬液。实验期间观察动物一般状况、饮水量、摄食量,体重变化,监测随机血糖。实验8周后处死小鼠,检测各组空腹血糖、胰岛素、血脂水平,HE染色对腹主动脉进行形态学观察,借助基因芯片技术对胸主动脉组织进行基因表达谱检测,筛选出差异表达基因,进行GO注释,Pathway分析,解释生物学意义。
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,体重较模型组下降,血糖、血脂较模型组降低。参芪复方组与模型组差异表达基因,经GO注释、Pathway分析,主要涉及细胞命运确定、细胞定位、大分子代谢过程和胰岛素信号通路、脂肪细胞因子信号通路、半胱氨酸和蛋氨酸代谢通路；涉及到Kdr、FGFR4、Met、AMPK基因。
结论：参芪复方可以改善糖尿病大血管病变KKAy小鼠的一般状态,减少模型小鼠的饮水量,降低模型小鼠体重,改善脂代谢紊乱,减轻模型小鼠血管内皮损伤,延缓糖尿病动脉硬化的进展。其作用机理可能是通过调控生物学过程细胞命运确定、细胞定位、大分子代谢过程和胰岛素信号通路、脂肪细胞因子信号通路、半胱氨酸和蛋氨酸代谢通路及Kdr、FGFR4、Met、AMPK基因,促进糖尿病大血管病变早期受损内皮细胞修复,减少半胱氨酸和蛋氨酸代谢产物同型半胱氨酸对血管的损害,从而防治糖尿病大血管病变。
Objective: Through observing the effect of ShenQi Compound Recipe, which has the function of supplementing Qi and Yin, and promoting the blood circulation, on the aortic pathological morphology of KKAy mice with diabetic vascular disease, and finding the molecular targets of prevention and treatment of diabetic macroangiopathies, by using the gene chip technology, we explored the biological effects and mechanisms, and providing the molecular basis of ShenQi Compound Recipe in preventing diabetic macroangiopathies.
Methods:66male KKAy mice,18-20weeks old, random blood glucose>13.9mmol/l, were divided to four groups:the KKAy group, diabetic macrovascular disease group, the ShenQi Compuound Prescription group, and rosiglitazone group, each group had15mice.15Normal C57BL/6J mice were set as normal group. The model group, ShenQi Compuound Prescription group and rosiglitazone group mice were induced by adding The Nco-nitrio-L-arginine methyl ester (L-NAME) with0.2mg. ml-1.d-1into the drinking water for8weeks. The normal group were fed with normal diet, while others with high fat diat. At the same time, ShenQi Compuound Prescription were administered ShenQi compound recipe with14.4g·kg-1·d-1, and rosiglitazone group was administered rosiglitazone suspension with1.33mg. kg-1.d-1, while others were administered physiological saline with10ml. kg-1.d-1. In the experimental period, general status were observed as well as the amount of water drinking, food intake, body weight, and random blood glucose. After8weeks, the mice were sacrificed to detect the fasting blood glucose, insulin, lipid levels, HE Staining in abdominal aortic for observing aortic morphology, detecting the gene expression profiles of the Thoracic aorta by microarray gene protein technique, Screening the differentially expressed genes, GO annotations, Pathway analysis, and explaining the biological significance.
Results:the general state of ShenQi Compound Recipe group were better than that of model group, with drinking less, body weight being decreased, as well as blood glucose, blood lipids. The Differentially expressed genes of ShenQi Compound Recipe group,compared with the model group, through GO annotation, pathway analysis, mainly involved in cell fate commitment, localization of cell, and macromolecule metabolic processes, as well as the Insulin signaling pathway, Adipocytokine signaling pathway and Cysteine and methionine metabolism, and the gene involved were Kdr、FGFR4、Met、AMPK.
Conclusion: ShenQi Compound Recipes can improve the general state of KKAy mice with diabetic macrovascular disease, reducing the amount of drinking water of the model mice, reducing the body weight, improving lipid metabolism disorders, alleviating the vascular endothelial injury, delaying the progress of atherosclerosis. The mechanism may be repairing the damaged endothelial cells in the early stage of diabetic macrovascular disease, reducing the damage to blood vesssel of Homocysteine, Metabolites of Cysteine and methionine, through regulating cell fate commitment, localization of cell, macromolecule metabolism, as well as the Insulin signaling pathway, Adipocytokine signaling pathway,Cysteine and methionine metabolic signaling, as well as genes such as Kdr、FGFR4、Met、AMPK.
方法：66只随机血糖2次≥13.9mmol·L-1的18-20周龄雄性KKAy小鼠随机分成4组：KKAy组(n=15)；糖尿病大血管病变模型组(简称模型组,n=15)；参芪复方组(n=15)；罗格列酮组(n=15)。正常C57BL/6J小鼠(n=15)做对照组。其中模型组、参芪复方组及罗格列酮组予以一氧化氮合成酶(eNOS)抑制剂(L-NAME)0.2mg-ml-1·d-1加入饮用水中进行造模,连续造模8周。正常组喂普通饲料,各实验组KKAy小鼠喂高脂饲料。造模同时给予药物治疗,正常组、KKAy组、模型组均按10ml·kg-1·d-1灌服生理盐水,中药组按14.4g·kg-1·d-1灌服参芪复方浸膏,罗格列酮组按1.33mg·kg-l·d-1灌服罗格列酮悬液。实验期间观察动物一般状况、饮水量、摄食量,体重变化,监测随机血糖。实验8周后处死小鼠,检测各组空腹血糖、胰岛素、血脂水平,HE染色对腹主动脉进行形态学观察,借助基因芯片技术对胸主动脉组织进行基因表达谱检测,筛选出差异表达基因,进行GO注释,Pathway分析,解释生物学意义。
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,体重较模型组下降,血糖、血脂较模型组降低。参芪复方组与模型组差异表达基因,经GO注释、Pathway分析,主要涉及细胞命运确定、细胞定位、大分子代谢过程和胰岛素信号通路、脂肪细胞因子信号通路、半胱氨酸和蛋氨酸代谢通路；涉及到Kdr、FGFR4、Met、AMPK基因。
结论：参芪复方可以改善糖尿病大血管病变KKAy小鼠的一般状态,减少模型小鼠的饮水量,降低模型小鼠体重,改善脂代谢紊乱,减轻模型小鼠血管内皮损伤,延缓糖尿病动脉硬化的进展。其作用机理可能是通过调控生物学过程细胞命运确定、细胞定位、大分子代谢过程和胰岛素信号通路、脂肪细胞因子信号通路、半胱氨酸和蛋氨酸代谢通路及Kdr、FGFR4、Met、AMPK基因,促进糖尿病大血管病变早期受损内皮细胞修复,减少半胱氨酸和蛋氨酸代谢产物同型半胱氨酸对血管的损害,从而防治糖尿病大血管病变。
Objective: Through observing the effect of ShenQi Compound Recipe, which has the function of supplementing Qi and Yin, and promoting the blood circulation, on the aortic pathological morphology of KKAy mice with diabetic vascular disease, and finding the molecular targets of prevention and treatment of diabetic macroangiopathies, by using the gene chip technology, we explored the biological effects and mechanisms, and providing the molecular basis of ShenQi Compound Recipe in preventing diabetic macroangiopathies.
Methods:66male KKAy mice,18-20weeks old, random blood glucose>13.9mmol/l, were divided to four groups:the KKAy group, diabetic macrovascular disease group, the ShenQi Compuound Prescription group, and rosiglitazone group, each group had15mice.15Normal C57BL/6J mice were set as normal group. The model group, ShenQi Compuound Prescription group and rosiglitazone group mice were induced by adding The Nco-nitrio-L-arginine methyl ester (L-NAME) with0.2mg. ml-1.d-1into the drinking water for8weeks. The normal group were fed with normal diet, while others with high fat diat. At the same time, ShenQi Compuound Prescription were administered ShenQi compound recipe with14.4g·kg-1·d-1, and rosiglitazone group was administered rosiglitazone suspension with1.33mg. kg-1.d-1, while others were administered physiological saline with10ml. kg-1.d-1. In the experimental period, general status were observed as well as the amount of water drinking, food intake, body weight, and random blood glucose. After8weeks, the mice were sacrificed to detect the fasting blood glucose, insulin, lipid levels, HE Staining in abdominal aortic for observing aortic morphology, detecting the gene expression profiles of the Thoracic aorta by microarray gene protein technique, Screening the differentially expressed genes, GO annotations, Pathway analysis, and explaining the biological significance.
Results:the general state of ShenQi Compound Recipe group were better than that of model group, with drinking less, body weight being decreased, as well as blood glucose, blood lipids. The Differentially expressed genes of ShenQi Compound Recipe group,compared with the model group, through GO annotation, pathway analysis, mainly involved in cell fate commitment, localization of cell, and macromolecule metabolic processes, as well as the Insulin signaling pathway, Adipocytokine signaling pathway and Cysteine and methionine metabolism, and the gene involved were Kdr、FGFR4、Met、AMPK.
Conclusion: ShenQi Compound Recipes can improve the general state of KKAy mice with diabetic macrovascular disease, reducing the amount of drinking water of the model mice, reducing the body weight, improving lipid metabolism disorders, alleviating the vascular endothelial injury, delaying the progress of atherosclerosis. The mechanism may be repairing the damaged endothelial cells in the early stage of diabetic macrovascular disease, reducing the damage to blood vesssel of Homocysteine, Metabolites of Cysteine and methionine, through regulating cell fate commitment, localization of cell, macromolecule metabolism, as well as the Insulin signaling pathway, Adipocytokine signaling pathway,Cysteine and methionine metabolic signaling, as well as genes such as Kdr、FGFR4、Met、AMPK.
引文
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