罗格列酮和复方丹参滴丸对糖尿病大鼠心肌病变的保护作用
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摘要
糖尿病心肌病(diabetic cardiomyopathy, DC)是糖尿病(diabetic mellitus, DM)引起心脏微血管病变和心肌代谢紊乱所致的心肌广泛局灶性坏死病变。目前认为糖尿病诱发的炎症因子通过氧化应激反应所诱发的心肌细胞死亡是DC发生发展中的重要始动因子,而炎症因子会影响水通道(aquaporin, AQP)的表达。我们通过前期大鼠实验,已经证实AQP1和AQP3蛋白在大鼠心肌组织的表达,本研究第一部分先讨论糖尿病心肌病状态下,AQP1和AQP3在心肌组织的表达和调控变化。首先,高脂高糖饮食联合小剂量多次腹腔注射链脲佐菌素(streptocin, STZ),建立以胰岛素抵抗(insulinresistance, IR)为特征的2型糖尿病大鼠模型,8周后通过生化检测和组织形态学研究来观察心肌病变的特点,并通过免疫组织化学、Western blotting方法测定心肌组织AQP1、AQP3蛋白的变化,结果模型组血糖、血脂、心肌酶明显升高,AQP1、AQP3蛋白以相同的糖化形式表达,表达定位没有改变,但蛋白量减少,其有可能是机体对心肌病病理改变的保护性反馈调节。本研究第二部分以刚建立2型糖尿病模型的大鼠为研究对象,进行罗格列酮(Rosiglitazone, RSG)、复方丹参滴丸(Danshen dripping pill, DSP)治疗8周,与模型组相比较,8周后给药组胰岛素抵抗指数、血糖、血脂、心肌酶、超敏C-反应蛋白(highsensitivity C-reactive protein, HS-CRP)均有所降低,心肌组织中丙二醛(malondialdehyde,MDA)含量有所降低、超氧化物歧化酶(superoxide dismutase, SOD)活性有所恢复,可稳定胞膜AQP1和AQP3蛋白的表达,以大剂量组和两药小剂量联合组疗效更为显著,有统计学意义。
In recent years, It was reported that the incidence of diabetes mellitus has dramatically increased in China, of which about 95% for type 2 diabetes, and has endanged the human life, so people have paid more attention to the prevention and cure of it. As we have known, the harm of diabetes is determined by various chronic complications, among which heart lesion is the most serious. A large number of studies have confirmed that diabetic cardiomyopathy is an independent state of pathological physiology and the main course of heart failure and mortality.
The pathogenesis of diabetic cardiomyopathy, is complicated and not fully understood, thought the interaction of various factors such as metabolic disorder, insulin resistance, oxidative stress, vascular lesions. In addition, the theory of inflammation is concerned recently. Inflammatory reaction has been increased by obesity because of excessive intake of nutrient in the early stage of type 2 diabetes. As a result, inflammatory cytokines in conjunction with the diabetes, by causing oxidative stress and cell death, have a bad effect on the cardiovascular system in a systemic and local way. Furthermore, it has been confirmed that the role of oxidative stress, causing a vicious metabolic cycle, leaded to the progression of complications such as diabetic cardiomyopathy, so only the strict control of blood glucose does not prevent progression of diabetic cardiomyopathy and other complications. There is an urgent need to develop an agent with protective effects on cardiovascular system and study its protective mechanisms to cardiovascular complications. Clinical observation and literatures have found that both Rosiglitazone and Danshen dripping pills have good effect on diabetes and complications. Rosiglitazone, a hypoglycemic agent of thiazolidinediones (TZDs), has attracted remarkable scientific interest on novel and potent improving insulin-sensitivity agents, and to lighten insulin resistance, more over, to have a protective effect on energy metabolic cycle and resist inflammation and so on. On the other hand, Danshen dripping pill composed of Salvia, three-seven and borneol, as traditional Chinese medicine, was first licensed by the FDA of U.S. to clinical trials and have been demonstrated, by pharmacological and molecular biological studies, to improve glucose and lipid metabolism, regulate vascular endothelial function and so on. However, the research, observing the effect of combination of tow drugs on diabetic cardiomyopathy, was vacant.
The studies have shown that inflammatory cytokines such as tumor necrosis factor-αand IFN-γhave increased the expressing of aquaporin(AQP). AQPs are a series of intrinsic homologous membrane proteins related to transporting water, widely existing in plants, animals and microorganisms, and it has been confirmed that a variety of AQPs are expressed in myocardial tissue including AQP1 and so on. Because AQPs in different organs have different biological functions, mamy disease may be related to the dysfunction of regulation and control of AQPs. Up to now, many progresses, on the location and physiological functions of AQPs, have been made in the human respiratory, nervous, digestive, urinary tract and other systems, but systematic research, on the expression and physiological functions AQPs in myocardial tissue, was still untaken. In the first topic, we will investigate the expression and regulation of AQP1 and AQP3 in rat myocardial tissue with diabetic cardiomyopathy.
We carried out some pre-experimental studies in rats, which have verified the expression of AQP1 and AQP3 in myocardial tissue. First of all, the methods that combined high sugar and high fat diet with STZ to establish type 2 diabetes model in rats with characteristics of insulin resistance. During the experiment, we regularly recorded general condition of all the rats such as weight, food intake, water intake, urine output, and detected fasting blood glucose. At the end of the experiment, the changes between two groups were observed by biochemical testing and histological study, and the expression and regulation of AQP1 and AQP3 in myocardial tissue was observed by the method of immuno-histochemistry and Western blotting. Our study found that:a model of type 2 diabetes in rats was created, which had characteristic of excessive drink, excessive food, excessive urine, fat, and metabolic disorders of sugar and fat, mimic patients in clinical; compared with the normal group, the rats showed typical diabetic cardiomyopathy after models having been established for 8 weeks:such as increasing release of myocardial enzymes and disorder of myofibril. Immunohistochemistry showed that:AQP1 was mainly expressed in the membrane of cardiac vascular endothelial cell and AQP3 was mainly expressed in the membrane of myocardial cell in normal rats; compared with the normal group, the specific staining of AQP1 and AQP3 in myocardial tissue was decreased, but had the same location in the diabetic cardiomyopathy tissues. In order to further determine the regulation of AQP1 and AQP3, Western blotting was used to test the expression of AQP1 and AQP3. Our results showed that:AQPl and AQP3 had the same glycosylated form in myocardial tissue of two groups. Results of quantitative analysis of AQP1 and AQP3 protein in myocardial tissue showed that:the amount of AQP1 and AQP3 protein in the diabetic cardiomyopathy tissues was significantly reduced compared with the normal group. This result confirmed the results mentioned above. The mechanism may be the protective feedback regulation of body to pathological changes of diabetic cardiomyopathy.
Finally, we observed effect of Rosiglitazone and Danshen dripping pill on the changes of expression and regulation of AQP1 and AQP3 in rat myocardial tissue and improved their protective effect on diabetic cardiomyopathy.The successful diabetes model rats were selected, and randomly divided into six groups:model group of diabetic cardiomyopathy, high and low dose group of Rosiglitazone and Danshen dripping pill, and low dose group of Rosiglitazone combined with Danshen dripping pill. After drug intervention for 8 weeks, changes were observed of sympathy, metabolic disorders, content of malondialdehyde and activity of superoxide dismutase in myocardial tissue, the expression and regulation of AQP1 and AQP3 proteins in myocardial tissue. The results showed that:compared with the model group, for low dose group of Rosiglitazone, there was significance in decreasing the level of HOMA-IR(P<0.05), FBG(P<0.05), serum lipids(P<0.05), serum enzymes(P<0.05, P＜0.01), Hs-CRP(P<0.05) and content of MDA(P<0.05), the activity of SOD and expression of AQP1 and AQP3 proteins in the membrane was increased; for high dose group of Rosiglitazone group, statistical significance has been improved(P<0.05, P<0.01); for low dose group of Danshen dripping pill, the level of FBG and serum lipids was decreased in a way of no significance, and there was significance in decreasing the level of HOMA-IR(P<0.05), serum enzymes(P<0.05, P＜0.01). Hs-CRP (P<0.05) and content of MDA(P<0.05), the activity of SOD and the expression of AQP1 and AQP3 proteins in the membrane was increased; for high dose group of Danshen dripping pill group, statistical significance has been improved (P<0.05, P<0.01); for low dose group of Rosiglitazone combined with Danshen dripping pill, there was significance in decreasing the level of HOMA-IR (P<0.01), FBG(P<0.01), serum lipids(P<0.05, P<0.01), serum enzymes(P<0.01), Hs-CRP(P＜0.01) and content of MDA (P＜0.01), the activity of SOD and the expression of AQP1 and AQP3 proteins in the membrane was increased.
As relation above, we concluded that:①AQP1 was mainly expressed in the membrane of cardiac vascular endothelial cell and AQP3 was mainly expressed in the membrane of myocardial cell in normal rats;②the same location was observed in the diabetic cardiomyopathy tissues, but the amount of AQP1 and AQP3 proteins in myocardial tissue was decreased, the regulatory mechanisms of which remains to be further studied;③The result of blood biochemical testing suggested that Rosiglitazone and Danshen dripping pill relieved the metabolic disorder, protected myocardial cells and vascular endothelium by decreasing insulin resist, improving glucose and lipid metabolism and decreasing release of myocardial enzymes and level of Hs-CRP;④Rosiglitazone and Danshen dripping pill had been demonstrated, by analysising content of MDA and activity of SOD, to resisting oxygen free radicals and Lipid peroxidation in myocardial tissue;⑤Rosiglitazone and Danshen dripping pill showed protective effect on diabetic cardiomyopathy by upregulating expression of AQP1 and AQP3 proteins. There was more significance for high-dose group and combined group. The observation of two drugs regulating the expression of AQP1 and AQP3 proteins for different time and the precise molecular mechanism remains to be further studied.
In recent years, It was reported that the incidence of diabetes mellitus has dramatically increased in China, of which about 95% for type 2 diabetes, and has endanged the human life, so people have paid more attention to the prevention and cure of it. As we have known, the harm of diabetes is determined by various chronic complications, among which heart lesion is the most serious. A large number of studies have confirmed that diabetic cardiomyopathy is an independent state of pathological physiology and the main course of heart failure and mortality.
The pathogenesis of diabetic cardiomyopathy, is complicated and not fully understood, thought the interaction of various factors such as metabolic disorder, insulin resistance, oxidative stress, vascular lesions. In addition, the theory of inflammation is concerned recently. Inflammatory reaction has been increased by obesity because of excessive intake of nutrient in the early stage of type 2 diabetes. As a result, inflammatory cytokines in conjunction with the diabetes, by causing oxidative stress and cell death, have a bad effect on the cardiovascular system in a systemic and local way. Furthermore, it has been confirmed that the role of oxidative stress, causing a vicious metabolic cycle, leaded to the progression of complications such as diabetic cardiomyopathy, so only the strict control of blood glucose does not prevent progression of diabetic cardiomyopathy and other complications. There is an urgent need to develop an agent with protective effects on cardiovascular system and study its protective mechanisms to cardiovascular complications. Clinical observation and literatures have found that both Rosiglitazone and Danshen dripping pills have good effect on diabetes and complications. Rosiglitazone, a hypoglycemic agent of thiazolidinediones (TZDs), has attracted remarkable scientific interest on novel and potent improving insulin-sensitivity agents, and to lighten insulin resistance, more over, to have a protective effect on energy metabolic cycle and resist inflammation and so on. On the other hand, Danshen dripping pill composed of Salvia, three-seven and borneol, as traditional Chinese medicine, was first licensed by the FDA of U.S. to clinical trials and have been demonstrated, by pharmacological and molecular biological studies, to improve glucose and lipid metabolism, regulate vascular endothelial function and so on. However, the research, observing the effect of combination of tow drugs on diabetic cardiomyopathy, was vacant.
The studies have shown that inflammatory cytokines such as tumor necrosis factor-αand IFN-γhave increased the expressing of aquaporin(AQP). AQPs are a series of intrinsic homologous membrane proteins related to transporting water, widely existing in plants, animals and microorganisms, and it has been confirmed that a variety of AQPs are expressed in myocardial tissue including AQP1 and so on. Because AQPs in different organs have different biological functions, mamy disease may be related to the dysfunction of regulation and control of AQPs. Up to now, many progresses, on the location and physiological functions of AQPs, have been made in the human respiratory, nervous, digestive, urinary tract and other systems, but systematic research, on the expression and physiological functions AQPs in myocardial tissue, was still untaken. In the first topic, we will investigate the expression and regulation of AQP1 and AQP3 in rat myocardial tissue with diabetic cardiomyopathy.
We carried out some pre-experimental studies in rats, which have verified the expression of AQP1 and AQP3 in myocardial tissue. First of all, the methods that combined high sugar and high fat diet with STZ to establish type 2 diabetes model in rats with characteristics of insulin resistance. During the experiment, we regularly recorded general condition of all the rats such as weight, food intake, water intake, urine output, and detected fasting blood glucose. At the end of the experiment, the changes between two groups were observed by biochemical testing and histological study, and the expression and regulation of AQP1 and AQP3 in myocardial tissue was observed by the method of immuno-histochemistry and Western blotting. Our study found that:a model of type 2 diabetes in rats was created, which had characteristic of excessive drink, excessive food, excessive urine, fat, and metabolic disorders of sugar and fat, mimic patients in clinical; compared with the normal group, the rats showed typical diabetic cardiomyopathy after models having been established for 8 weeks:such as increasing release of myocardial enzymes and disorder of myofibril. Immunohistochemistry showed that:AQP1 was mainly expressed in the membrane of cardiac vascular endothelial cell and AQP3 was mainly expressed in the membrane of myocardial cell in normal rats; compared with the normal group, the specific staining of AQP1 and AQP3 in myocardial tissue was decreased, but had the same location in the diabetic cardiomyopathy tissues. In order to further determine the regulation of AQP1 and AQP3, Western blotting was used to test the expression of AQP1 and AQP3. Our results showed that:AQPl and AQP3 had the same glycosylated form in myocardial tissue of two groups. Results of quantitative analysis of AQP1 and AQP3 protein in myocardial tissue showed that:the amount of AQP1 and AQP3 protein in the diabetic cardiomyopathy tissues was significantly reduced compared with the normal group. This result confirmed the results mentioned above. The mechanism may be the protective feedback regulation of body to pathological changes of diabetic cardiomyopathy.
Finally, we observed effect of Rosiglitazone and Danshen dripping pill on the changes of expression and regulation of AQP1 and AQP3 in rat myocardial tissue and improved their protective effect on diabetic cardiomyopathy.The successful diabetes model rats were selected, and randomly divided into six groups:model group of diabetic cardiomyopathy, high and low dose group of Rosiglitazone and Danshen dripping pill, and low dose group of Rosiglitazone combined with Danshen dripping pill. After drug intervention for 8 weeks, changes were observed of sympathy, metabolic disorders, content of malondialdehyde and activity of superoxide dismutase in myocardial tissue, the expression and regulation of AQP1 and AQP3 proteins in myocardial tissue. The results showed that:compared with the model group, for low dose group of Rosiglitazone, there was significance in decreasing the level of HOMA-IR(P<0.05), FBG(P<0.05), serum lipids(P<0.05), serum enzymes(P<0.05, P＜0.01), Hs-CRP(P<0.05) and content of MDA(P<0.05), the activity of SOD and expression of AQP1 and AQP3 proteins in the membrane was increased; for high dose group of Rosiglitazone group, statistical significance has been improved(P<0.05, P<0.01); for low dose group of Danshen dripping pill, the level of FBG and serum lipids was decreased in a way of no significance, and there was significance in decreasing the level of HOMA-IR(P<0.05), serum enzymes(P<0.05, P＜0.01). Hs-CRP (P<0.05) and content of MDA(P<0.05), the activity of SOD and the expression of AQP1 and AQP3 proteins in the membrane was increased; for high dose group of Danshen dripping pill group, statistical significance has been improved (P<0.05, P<0.01); for low dose group of Rosiglitazone combined with Danshen dripping pill, there was significance in decreasing the level of HOMA-IR (P<0.01), FBG(P<0.01), serum lipids(P<0.05, P<0.01), serum enzymes(P<0.01), Hs-CRP(P＜0.01) and content of MDA (P＜0.01), the activity of SOD and the expression of AQP1 and AQP3 proteins in the membrane was increased.
As relation above, we concluded that:①AQP1 was mainly expressed in the membrane of cardiac vascular endothelial cell and AQP3 was mainly expressed in the membrane of myocardial cell in normal rats;②the same location was observed in the diabetic cardiomyopathy tissues, but the amount of AQP1 and AQP3 proteins in myocardial tissue was decreased, the regulatory mechanisms of which remains to be further studied;③The result of blood biochemical testing suggested that Rosiglitazone and Danshen dripping pill relieved the metabolic disorder, protected myocardial cells and vascular endothelium by decreasing insulin resist, improving glucose and lipid metabolism and decreasing release of myocardial enzymes and level of Hs-CRP;④Rosiglitazone and Danshen dripping pill had been demonstrated, by analysising content of MDA and activity of SOD, to resisting oxygen free radicals and Lipid peroxidation in myocardial tissue;⑤Rosiglitazone and Danshen dripping pill showed protective effect on diabetic cardiomyopathy by upregulating expression of AQP1 and AQP3 proteins. There was more significance for high-dose group and combined group. The observation of two drugs regulating the expression of AQP1 and AQP3 proteins for different time and the precise molecular mechanism remains to be further studied.
引文
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