黄芪对糖尿病大鼠心肌中心肌营养素-1、血管紧张素-Ⅱ表达的影响
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摘要
目的：了解糖尿病大鼠心肌组织中心肌营养素-1(cardiotrophin-1, CT-1)mRNA、蛋白及心肌局部Ang-Ⅱ的表达,探讨心肌营养素-1是否参与了糖尿病心肌病变的发生及黄芪注射液改善糖尿病大鼠心肌病变的作用机制。
方法：30只健康雄性Wistar大鼠随机分为正常组(NC组,n=10)、糖尿病组(DM组,n=10)、黄芪干预组(AS组,n=10)。正常组喂养普通饲料(12%蛋白质,5%脂肪,67%碳水化合物,16%其他),糖尿病组及黄芪干预组喂养高糖高脂饲料(基础饲料中加入20%白糖、2.5%胆固醇、10%猪油、1.0%胆酸盐)。喂养6w后,糖尿病组及黄芪干预组一次性腹腔注射链脲佐菌素(STZ)30mg／kg,一周后测血糖,选随机血糖>16.7mmol／L并有多饮、多食、多尿者作为糖尿病模型。黄芪干预组每日以黄芪注射液8 g／kg灌胃,正常组、糖尿病组每日以等体积生理盐水灌胃。灌胃8周后处死大鼠,测定大鼠心脏指数(心脏重量／体重),Masson染色中以胶原容积分数(CVF)反映胶原的含量,(CVF=心肌胶原面积／所测视野面积),采用放射免疫的方法测定心肌组织中血管紧张素-Ⅱ的含量,用RT-PCR测定CT-1mRNA的表达,用免疫组化法检测CT-1的表达。
结果：1.实验末与正常组比较,糖尿病组和黄芪干预组甘油三酯、胆固醇、低密度脂蛋白水平升高(P<0.01),高密度脂蛋白水平下降(P<0.01)；与糖尿病组比较,黄芪干预组甘油三酯、胆固醇、低密度脂蛋白水平下降(P<0.05),高密度脂蛋白水平显著升高(P<0.05)。2.实验末糖尿病组和黄芪干预组血糖高于对照组(P<0.01)；心脏指数(心脏重量／体重)糖尿病组高于正常组(P<0.01),黄芪干预组心脏指数较糖尿病组降低(P<0.05)；Masson染色中以胶原容积分数(CVF)反映胶原的含量,糖尿病组高于正常组(P<0.01),黄芪干预组比糖尿病组减少(P<0.05)；2.糖尿病大鼠与正常大鼠相比心肌细胞肥大,排列紊乱,细胞核大小不甚规则,细胞浆相对淡染,心肌纤维排列紊乱、局灶性坏死,黄芪干预组大鼠亦存在心肌细胞和心肌纤维的坏死,较糖尿病组有所减轻。3.糖尿病组大鼠心肌组织中Ang-Ⅱ明显高于正常组大鼠(P<0.01),黄芪干预组较模型组减少,差异有统计学意义(P<0.05),CT-1mRNA及蛋白的表达糖尿病组高于正常组(P<0.01),黄芪干预组较模型组减少(P<0.01)。
结论：1、高糖高脂饲料喂养结合小剂量链脲佐菌素注射可成功复制糖尿病大鼠模型,且在糖尿病成模后8周大鼠出现了心肌的病变；2、CT-1mRNA和蛋白的及Ang-Ⅱ在糖尿病组中的表达是升高的,可能参与了糖尿病心肌病变的发生发展。黄芪注射液可以降低CT-1和Ang-Ⅱ的水平,其具体机制需进一步研究。总之,CT-1在糖尿病心肌病变的发生中起到一定作用,黄芪注射液可以减轻糖尿病大鼠的心肌病变,减少CT-1的表达,同时减少心肌组织中Ang-Ⅱ的表达。
Objective:To understand the diabetic rat model of myocardial tissue of Cardiotrophin-1(CT-1) mRNA and protein expression, Discussion whether the cardiotrophin-1 is involved in the occurrence of diabetic cardiomyopathy. To investigate the mechanism for Astragalus to improve the diabetic rat cardiac lesions in rats.
Methods:Male Wistar rats were randomly divided into normal group (n= 10) diabetic model group (n= 10) and astragalus group(n=10).The normal group were feeded with normal forage plants(12%protein,5%fat,67%sugar,16%else). Diabetic model group and astragalus group induced by high-fat diet (66.5%normal forage plants,20%sugar,2.5%cholesterin,10%lard,1.0%bile salt) and STZ (30mg/kg). Then astragalus group was given intragastric administration with astragalus at the dose of 8g/kg/d for 8 weeks. Take the weight of rat heart, calculate cardiac index in rats, determination of myocardial fiber content in rats. Using radioimmunoassay to measured the Ang-Ⅱcontent in myocardial tissue.The mRNA expressions of CT-1 was determined by RT-PCR, the protein expressions of CT-1 was determined by immunohistochemistry.
Results:1.Compared with normal group, triglyceride, cholesterol, low-density lipoprotein were significantly higher in the diabetes group and the astragalus group (P<0.01), high-density lipoprotein were lower in the diabetes group and the astragalus group (P<0.01). Compared with the diabetes group, triglyceride,cholester-ol,low-density lipoprotein were significantly lower(P<0.05) in the astragalus group, high-density lipoprotein was higher in the astragalus group (P<0.05).2. Compared with normal group, model group and astragalus group, showed higher FBG(P<0.01), Cardiac index showed higher in model group(P<0.01), The content of myocardial fiber, the mRNA and protein expression of CT-1 levels, Ang-Ⅱin myocardial showed higher in model group(P<0.01); In the astragalus group cardiac index, the content of myocardial fiber, Ang-Ⅱin myocardial, the mRNA and protein expression of CT-1 levels were alleviated than those in the model group.2. Compared with normal rat, model group has cardiomyocyte hypertrophy, and disorder;cell nuclei showed irregular shape, the cytoplasm has short staining, cardiac muscle fibers were disordered and has local necrosis, In the astragalus group, the cardiomyocyte and cardiac muscle fibers have necrosis,but compared with model group the situation were improved.
Conclusions:1. High-fat, high-sugar diet with low-dose streptozotocin injection can be successfully established diabetes rat model, and have a lower mortality, and the diabetes rats have the diabetic cardiomyopathy after 8 weeks.2.CT-1 mRNA and protein expression and Ang-Ⅱexpression were increased in model group,and play a certain role in the incidence of diabetic cardiomyopathy;3.Astragalus can significantly reduce the mRNA and protein expression of CT-1 in myocardial, while reducing the Ang-Ⅱexpression in myocardial tissue. In conclusion, CT-1 play a role in the occurrence of diabetic cardiomyopathy, Astragalus can reduce the cardiomyopathy in diabetic rats, and reduce the CT-1 expression, while reducing the Ang-Ⅱexpression in myocardial tissue.
方法：30只健康雄性Wistar大鼠随机分为正常组(NC组,n=10)、糖尿病组(DM组,n=10)、黄芪干预组(AS组,n=10)。正常组喂养普通饲料(12%蛋白质,5%脂肪,67%碳水化合物,16%其他),糖尿病组及黄芪干预组喂养高糖高脂饲料(基础饲料中加入20%白糖、2.5%胆固醇、10%猪油、1.0%胆酸盐)。喂养6w后,糖尿病组及黄芪干预组一次性腹腔注射链脲佐菌素(STZ)30mg／kg,一周后测血糖,选随机血糖>16.7mmol／L并有多饮、多食、多尿者作为糖尿病模型。黄芪干预组每日以黄芪注射液8 g／kg灌胃,正常组、糖尿病组每日以等体积生理盐水灌胃。灌胃8周后处死大鼠,测定大鼠心脏指数(心脏重量／体重),Masson染色中以胶原容积分数(CVF)反映胶原的含量,(CVF=心肌胶原面积／所测视野面积),采用放射免疫的方法测定心肌组织中血管紧张素-Ⅱ的含量,用RT-PCR测定CT-1mRNA的表达,用免疫组化法检测CT-1的表达。
结果：1.实验末与正常组比较,糖尿病组和黄芪干预组甘油三酯、胆固醇、低密度脂蛋白水平升高(P<0.01),高密度脂蛋白水平下降(P<0.01)；与糖尿病组比较,黄芪干预组甘油三酯、胆固醇、低密度脂蛋白水平下降(P<0.05),高密度脂蛋白水平显著升高(P<0.05)。2.实验末糖尿病组和黄芪干预组血糖高于对照组(P<0.01)；心脏指数(心脏重量／体重)糖尿病组高于正常组(P<0.01),黄芪干预组心脏指数较糖尿病组降低(P<0.05)；Masson染色中以胶原容积分数(CVF)反映胶原的含量,糖尿病组高于正常组(P<0.01),黄芪干预组比糖尿病组减少(P<0.05)；2.糖尿病大鼠与正常大鼠相比心肌细胞肥大,排列紊乱,细胞核大小不甚规则,细胞浆相对淡染,心肌纤维排列紊乱、局灶性坏死,黄芪干预组大鼠亦存在心肌细胞和心肌纤维的坏死,较糖尿病组有所减轻。3.糖尿病组大鼠心肌组织中Ang-Ⅱ明显高于正常组大鼠(P<0.01),黄芪干预组较模型组减少,差异有统计学意义(P<0.05),CT-1mRNA及蛋白的表达糖尿病组高于正常组(P<0.01),黄芪干预组较模型组减少(P<0.01)。
结论：1、高糖高脂饲料喂养结合小剂量链脲佐菌素注射可成功复制糖尿病大鼠模型,且在糖尿病成模后8周大鼠出现了心肌的病变；2、CT-1mRNA和蛋白的及Ang-Ⅱ在糖尿病组中的表达是升高的,可能参与了糖尿病心肌病变的发生发展。黄芪注射液可以降低CT-1和Ang-Ⅱ的水平,其具体机制需进一步研究。总之,CT-1在糖尿病心肌病变的发生中起到一定作用,黄芪注射液可以减轻糖尿病大鼠的心肌病变,减少CT-1的表达,同时减少心肌组织中Ang-Ⅱ的表达。
Objective:To understand the diabetic rat model of myocardial tissue of Cardiotrophin-1(CT-1) mRNA and protein expression, Discussion whether the cardiotrophin-1 is involved in the occurrence of diabetic cardiomyopathy. To investigate the mechanism for Astragalus to improve the diabetic rat cardiac lesions in rats.
Methods:Male Wistar rats were randomly divided into normal group (n= 10) diabetic model group (n= 10) and astragalus group(n=10).The normal group were feeded with normal forage plants(12%protein,5%fat,67%sugar,16%else). Diabetic model group and astragalus group induced by high-fat diet (66.5%normal forage plants,20%sugar,2.5%cholesterin,10%lard,1.0%bile salt) and STZ (30mg/kg). Then astragalus group was given intragastric administration with astragalus at the dose of 8g/kg/d for 8 weeks. Take the weight of rat heart, calculate cardiac index in rats, determination of myocardial fiber content in rats. Using radioimmunoassay to measured the Ang-Ⅱcontent in myocardial tissue.The mRNA expressions of CT-1 was determined by RT-PCR, the protein expressions of CT-1 was determined by immunohistochemistry.
Results:1.Compared with normal group, triglyceride, cholesterol, low-density lipoprotein were significantly higher in the diabetes group and the astragalus group (P<0.01), high-density lipoprotein were lower in the diabetes group and the astragalus group (P<0.01). Compared with the diabetes group, triglyceride,cholester-ol,low-density lipoprotein were significantly lower(P<0.05) in the astragalus group, high-density lipoprotein was higher in the astragalus group (P<0.05).2. Compared with normal group, model group and astragalus group, showed higher FBG(P<0.01), Cardiac index showed higher in model group(P<0.01), The content of myocardial fiber, the mRNA and protein expression of CT-1 levels, Ang-Ⅱin myocardial showed higher in model group(P<0.01); In the astragalus group cardiac index, the content of myocardial fiber, Ang-Ⅱin myocardial, the mRNA and protein expression of CT-1 levels were alleviated than those in the model group.2. Compared with normal rat, model group has cardiomyocyte hypertrophy, and disorder;cell nuclei showed irregular shape, the cytoplasm has short staining, cardiac muscle fibers were disordered and has local necrosis, In the astragalus group, the cardiomyocyte and cardiac muscle fibers have necrosis,but compared with model group the situation were improved.
Conclusions:1. High-fat, high-sugar diet with low-dose streptozotocin injection can be successfully established diabetes rat model, and have a lower mortality, and the diabetes rats have the diabetic cardiomyopathy after 8 weeks.2.CT-1 mRNA and protein expression and Ang-Ⅱexpression were increased in model group,and play a certain role in the incidence of diabetic cardiomyopathy;3.Astragalus can significantly reduce the mRNA and protein expression of CT-1 in myocardial, while reducing the Ang-Ⅱexpression in myocardial tissue. In conclusion, CT-1 play a role in the occurrence of diabetic cardiomyopathy, Astragalus can reduce the cardiomyopathy in diabetic rats, and reduce the CT-1 expression, while reducing the Ang-Ⅱexpression in myocardial tissue.
引文
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3.万磊,李菊香,罗伟等.心肌营养素-1与心室重塑,国外医学·老年医学分册,2008,29：75-78.
4.吕丹,张连峰等,心肌营养素-1生物学功能的多样性,中国比较医学杂志,2008,18：16-20.
5. ZvonicS, Hogan JC, Arbour-Reily P, et al, Effects of cardiotrophin on adipocytes, J Biol Chem 2004,279:47572-47579.
6.林楚佳,林少达,吴小英等,糖尿病伴高血压患者血浆心肌营养素-1的变化及作用,高血压杂志,2005,13：284-286.
7.林少达,林楚佳,黄天华等,2型糖尿病合并冠心病患者的促心肌素-1水平,中国糖尿病杂志,2007,15：233-234.
8.胡圣,张绪洪,董波等,氯沙坦及A779对糖尿病心肌病大鼠心肌间质纤维化的影响,山东大学学报(医学版),2008,46：362-365.
9. Liu J, Liu Z, Huang F, et al. Pioglitazone inhibits hypertrophy induced by high glucose and insulin in cultured neonatal rat cardiomyocytes, Pharmazie,2007,62:925-9.
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11.杨爽,陆莹,于波等,心肌营养素-1在血管紧张素致心肌细胞肥大中的表达,中国地方病学杂志,2006,25：359-362.
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1. David Stejskal, Viktor Ruzicka. CARDIOTROPHIN-1 REVIEW. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia,2008,152:9-19.
2.解辉,潘晓黎,吴伟等.糖尿病心肌病心肌细胞纤维化的病理改变,中华老年心脑血管病杂志,2008,10：374-376.
3.万磊,李菊香,罗伟等.心肌营养素-1与心室重塑,国外医学·老年医学分册,2008,29：75-78.
4.吕丹,张连峰等,心肌营养素-1生物学功能的多样性,中国比较医学杂志,2008,18：16-20.
5. ZvonicS, Hogan JC, Arbour-Reily P, et al, Effects of cardiotrophin on adipocytes, J Biol Chem 2004,279:47572-47579.
6.林楚佳,林少达,吴小英等,糖尿病伴高血压患者血浆心肌营养素-1的变化及作用,高血压杂志,2005,13：284-286.
7.林少达,林楚佳,黄天华等,2型糖尿病合并冠心病患者的促心肌素-1水平,中国糖尿病杂志,2007,15：233-234.
8.胡圣,张绪洪,董波等,氯沙坦及A779对糖尿病心肌病大鼠心肌间质纤维化的影响,山东大学学报(医学版),2008,46：362-365.
9. Liu J, Liu Z, Huang F, et al. Pioglitazone inhibits hypertrophy induced by high glucose and insulin in cultured neonatal rat cardiomyocytes, Pharmazie,2007,62:925-9.
10.吴伟,高俊杰,王荫炜等,心肌营养素-1和结缔组织增长因子在糖尿病大鼠心肌中的表达及厄贝沙坦的干预作用,中国组织化学与细胞化学杂志,2009,5：576-583.
11.杨爽,陆莹,于波等,心肌营养素-1在血管紧张素致心肌细胞肥大中的表达,中国地方病学杂志,2006,25：359-362.