Nrf2在病毒性心肌炎小鼠中的作用及葛根素干预的研究
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摘要
病毒性心肌炎（Viral myocarditis，VMC）是小儿心血管系统中最常见疾病，临床表现轻重不一，大多病人临床表现较轻，治疗效果较好，但有部分患儿发展成为慢性心肌炎，甚至进展为扩张型心肌病，病死率高，VMC是儿童后天性心脏病的主要病因之一，严重威胁着少年儿童的身体健康。近年来，VMC的发病呈现增高趋势，因此，引起学术界的普遍关注。VMC的发病机制至今尚未完全清楚，但普遍认为与病毒的直接损害、免疫机制、脂质过氧化介导的心肌损伤、心肌细胞凋亡及心肌纤维化有关，其中细胞因子起了非常重要的作用。目前对VMC的治疗没有特异性的治疗药物。核因子相关因子2(NF-E2-related factor2, Nrf2)是近年来新发现的一个转录因子，在心血管系统中表达稳定，研究表明Nrf2的目的基因在心血管系统疾病中具有保护作用。因此，我们推测，Nrf2可能参与了VMC的发生、发展过程。中药在VMC中越来越受到重视，葛根素(puerarin, Pue)普遍应用于成人心血管疾病的治疗，但它对心血管起保护作用机理尚不完全清楚，在儿童VMC中的临床应用经验相对较少，剂量也没有统一的规定。
本研究主要针对Nrf2在VMC中抗氧化、抗凋亡、抗纤维化方面进行研究，并探索Pue在这些方面所起的作用，以及大剂量应用导致的不良反应。将250只BALB/c纯种4周龄雄性小鼠，体重15±2g，随机分组对照组（20只），VMC组（30只），Nrf2激活剂5,6-二氢-1,2-二硫杂环戊烯-3-硫酮(5,6-dihydrocyclopenta-1,2-dithiole-3-thione,CPDT)25μM组（20只）、50μM组（20只）、75μM组（20只），不同剂量Pue组：5mg.kg-1（20只）、15mg.kg-1组（20只）、45mg.kg-1组（20只）、30mg.kg-1组（20只）、100mg.kg-1组（30只）、300mg.kg-1组（30只），用柯萨奇B3型病毒（CVB3），通过VMC经典造模方法进行造模。分别在实验第0、4、7、14、28天采血、杀鼠，留取心肌组织。采用流式细胞术检测小鼠心肌细胞的凋亡情况，应用Real-Time PCR法检测Nrf2mRNA、HO-1mRNA、Fas mRNA、TGF-β1mRNA的水平及用Western blot法检测Nrf2、 HO-1、Fas、TGF-β1的蛋白表达情况。
结果发现，Nrf2mRNA及其蛋白在各组均有表达，随着激活剂CPDT浓度及Pue给药剂量的增加，表达增强，在一定范围内呈浓度或剂量依赖性。给予大剂量Pue(≥100mg.kg-1)时，剂量依赖关系被打破，Nrf2呈现持续升高或不降低状态；CPDT及Pue组HO-1的转录及蛋白表达明显升高，且与Nrf2呈正相关。在一定Pue剂量梯度（≤45mg.kg-1）下，HO-1的转录及蛋白表达呈剂量依赖性,给予大剂量Pue(≥100mg.kg-1)时，剂量依赖关系被打破；CPDT及Pue组心肌细胞凋亡数减少，Nrf2与Fas呈负相关；Pue100mg.kg-1组、Pue300mg.kg-1组与VMC组比较无明显差异(P＞0.05)，提示给药剂量增加，治疗作用并没有相应增强；CPDT及Pue组中TGF-β1在一定的浓度或剂量梯度下，随着浓度/剂量的增大，TGF-β1表达降低，Nrf2与TGF-β1呈负相关；当Pue剂量增大到一定程度(≥100mg.kg-1)时，TGF-β1表达不降反而升高。对应用大剂量葛根素的研究发现，小鼠出现了明显的腹泻症状，小鼠死亡率明显升高，CK-MB水平显著增高、心肌病理变化严重，Nrf2、HO-1、Fas、TGF-β1mRNA及蛋白表达水平出现变化；Nrf2与HO-1间、Nrf2与Fas间、Nrf2与TGF-β1无相关性。
因此我们得出：Nrf2在VMC中表达增高，参与了VMC的发生、发展过程；Nrf2在VMC中具有抗氧化、抗心肌细胞凋亡、抗心肌纤维化的作用；Pue对VMC的治疗作用可能是通过激活Nrf2起作用，但同时可能存在其他途径发挥抗氧化、抗凋亡、抗纤维化作用；大剂量应用Pue时，治疗作用无相应增加，反而出现腹泻不良反应。
Viral myocarditis (Viral myocarditis, VMC) is the most common disease in thepediatric cardiovascular system, severity of its clinical manifestations is different, mostpatients are lighter, The therapeutic effect is better, but some children develop into chronicmyocarditis, or even progress dilated cardiomyopathy, high mortality. VMC is one of themajor cause of acquired heart disease in children, a serious threat to the physical health ofthe children. In recent years, VMC incidence show a higher trend, therefore, causedwidespread concerned. VMC pathogenesis has not yet fully clear, but generally agreed thatthe presence of the virus in the direct damage, myocardial injury, immune mechanisms anddamage of lipid peroxidation mediated, myocardial apoptosis and myocardial fibrosis. Cytokineplays a very important role in these processes. Currently there is not specific drug for VMCtreatment. Nuclear factor-related factor2(NF-E2-related factor2, Nrf2) is a newlydiscovered transcription factor that express stable in the cardiovascular system, studies haveshown that its target gene has a protective effect in cardiovascular diseases. Therefore, wehypothesized that Nrf2may be involved in the occurrence and development process of VMC.Traditional Chinese medicine was attentioned more and more in the VMC, the pueraringenerally applied to the treatment of adult cardiovascular disease, but its cardiovascularprotective mechanism of action is not fully understood, relatively few clinical experience forVMC in children, the dose also no unified requirements.
The study focuses on antioxidant, anti-apoptotic, anti-fibrotic of Nrf2in VMC andexplore the role of puerarin in these areas, and high-dose applications led to the adversereaction.250BALB/c purebred4-week-old male mice weighing15±2g, randomized to thecontrol group (20), VMC group (30), the Nrf2activator CPDT of25μM groups (20),50μM(20),75μM (20), different doses of puerarin（Pue）5mg.kg-1group (20),15mg.kg-1group (20),45mg.kg-1group (20),30mg.kg-1group (20),100mg.kg-1group (30),300mg.kg-1group (30).We made model with Coxsackie B3virus (CVB3) isolates by the method of the VMCclassical. Experimental day0,4,7,14,28, we blooded, killed mice and specimens frommyocardial tissue for subsequent experiments. Myocardial cell apoptosis of mice wasdetected with flow cytometry in each group, the application of the Real-Time PCR assayNrf2mRNA, HO-1mRNA, Fas mRNA and TGF-β1mRNA level of transcription and detected protein expression of Nrf2, HO-1, Fas and TGF-β1by Western blot.
We found that Nrf2mRNA and Nrf2protein expression increased with concentration of CPDT (Nrf2activator) and Pue dose increase in each group, showed a concentration or dose-dependent mannerwithin a certain range. Given large doses of Pue (≥100mg.kg-1), a dose-dependentrelationship is broken, Nrf2showing persistently elevated or no reduced state，that HO-1mRNA and protein expression was significantly increased in CPDT and Pue groups, HO-1and Nrf2were positively correlated. Within a certain range （≤45mg.kg-1）, HO-1transcription and protein expression showed a concentration or dose-dependent manner.Given large doses of Pue (≥100mg.kg-1), a dose-dependent relationship was broken, that thenumber of apoptotic cells was decrease in CPDT and Pue group from the cells, mRNA andprotein levels. Nrf2and Fas was negatively correlated. Compared Pue100mg.kg-1groupand Pue300mg·kg-1with VMC group, it showed no significant difference (P＞0.05),Which suggested therapeutic effect of the drug was not increase accordingly with the doseincreasing, that TGF-beta1mRNA and protein expression decreased in a certainconcentration or dose gradient in CPDT and Pue groups. Nrf2and TGF-beta1was negativelycorrelated. When Pue dose increased to a certain extent (≥100mg.kg-1), TGF-beta1expression did not fall but rise. We observed that high-dose Pue does not increase the role ofdrug treatment, but there is a clear diarrhea in mice, significantly increased mortality in mice,CK-MB level was significantly higher, myocardial pathological changes serious. Nrf2, HO-1,Fas, TGF-beta1mRNA and protein expression levels were change, Nrf2and HO-1, Nrf2andFas, Nrf2and TGF-beta1was no correlation.
Therefore, we concluded that Nrf2expression was elevated in VMC mice, and involvedin the occurrence and development of the VMC. Nrf2had effects of antioxidant, inhibittingmyocardial apoptosis and myocardial fibrosis in the VMC. Puerarin may be antioxidativedamage, anti-cardiomyocyte apoptosis and anti-myocardial fibrosis through activating Nrf2in VMC. But It may be has other ways to play these role at the same time. Large dosepuerarin increased adverse drug reactions of diarrhea.
本研究主要针对Nrf2在VMC中抗氧化、抗凋亡、抗纤维化方面进行研究，并探索Pue在这些方面所起的作用，以及大剂量应用导致的不良反应。将250只BALB/c纯种4周龄雄性小鼠，体重15±2g，随机分组对照组（20只），VMC组（30只），Nrf2激活剂5,6-二氢-1,2-二硫杂环戊烯-3-硫酮(5,6-dihydrocyclopenta-1,2-dithiole-3-thione,CPDT)25μM组（20只）、50μM组（20只）、75μM组（20只），不同剂量Pue组：5mg.kg-1（20只）、15mg.kg-1组（20只）、45mg.kg-1组（20只）、30mg.kg-1组（20只）、100mg.kg-1组（30只）、300mg.kg-1组（30只），用柯萨奇B3型病毒（CVB3），通过VMC经典造模方法进行造模。分别在实验第0、4、7、14、28天采血、杀鼠，留取心肌组织。采用流式细胞术检测小鼠心肌细胞的凋亡情况，应用Real-Time PCR法检测Nrf2mRNA、HO-1mRNA、Fas mRNA、TGF-β1mRNA的水平及用Western blot法检测Nrf2、 HO-1、Fas、TGF-β1的蛋白表达情况。
结果发现，Nrf2mRNA及其蛋白在各组均有表达，随着激活剂CPDT浓度及Pue给药剂量的增加，表达增强，在一定范围内呈浓度或剂量依赖性。给予大剂量Pue(≥100mg.kg-1)时，剂量依赖关系被打破，Nrf2呈现持续升高或不降低状态；CPDT及Pue组HO-1的转录及蛋白表达明显升高，且与Nrf2呈正相关。在一定Pue剂量梯度（≤45mg.kg-1）下，HO-1的转录及蛋白表达呈剂量依赖性,给予大剂量Pue(≥100mg.kg-1)时，剂量依赖关系被打破；CPDT及Pue组心肌细胞凋亡数减少，Nrf2与Fas呈负相关；Pue100mg.kg-1组、Pue300mg.kg-1组与VMC组比较无明显差异(P＞0.05)，提示给药剂量增加，治疗作用并没有相应增强；CPDT及Pue组中TGF-β1在一定的浓度或剂量梯度下，随着浓度/剂量的增大，TGF-β1表达降低，Nrf2与TGF-β1呈负相关；当Pue剂量增大到一定程度(≥100mg.kg-1)时，TGF-β1表达不降反而升高。对应用大剂量葛根素的研究发现，小鼠出现了明显的腹泻症状，小鼠死亡率明显升高，CK-MB水平显著增高、心肌病理变化严重，Nrf2、HO-1、Fas、TGF-β1mRNA及蛋白表达水平出现变化；Nrf2与HO-1间、Nrf2与Fas间、Nrf2与TGF-β1无相关性。
因此我们得出：Nrf2在VMC中表达增高，参与了VMC的发生、发展过程；Nrf2在VMC中具有抗氧化、抗心肌细胞凋亡、抗心肌纤维化的作用；Pue对VMC的治疗作用可能是通过激活Nrf2起作用，但同时可能存在其他途径发挥抗氧化、抗凋亡、抗纤维化作用；大剂量应用Pue时，治疗作用无相应增加，反而出现腹泻不良反应。
Viral myocarditis (Viral myocarditis, VMC) is the most common disease in thepediatric cardiovascular system, severity of its clinical manifestations is different, mostpatients are lighter, The therapeutic effect is better, but some children develop into chronicmyocarditis, or even progress dilated cardiomyopathy, high mortality. VMC is one of themajor cause of acquired heart disease in children, a serious threat to the physical health ofthe children. In recent years, VMC incidence show a higher trend, therefore, causedwidespread concerned. VMC pathogenesis has not yet fully clear, but generally agreed thatthe presence of the virus in the direct damage, myocardial injury, immune mechanisms anddamage of lipid peroxidation mediated, myocardial apoptosis and myocardial fibrosis. Cytokineplays a very important role in these processes. Currently there is not specific drug for VMCtreatment. Nuclear factor-related factor2(NF-E2-related factor2, Nrf2) is a newlydiscovered transcription factor that express stable in the cardiovascular system, studies haveshown that its target gene has a protective effect in cardiovascular diseases. Therefore, wehypothesized that Nrf2may be involved in the occurrence and development process of VMC.Traditional Chinese medicine was attentioned more and more in the VMC, the pueraringenerally applied to the treatment of adult cardiovascular disease, but its cardiovascularprotective mechanism of action is not fully understood, relatively few clinical experience forVMC in children, the dose also no unified requirements.
The study focuses on antioxidant, anti-apoptotic, anti-fibrotic of Nrf2in VMC andexplore the role of puerarin in these areas, and high-dose applications led to the adversereaction.250BALB/c purebred4-week-old male mice weighing15±2g, randomized to thecontrol group (20), VMC group (30), the Nrf2activator CPDT of25μM groups (20),50μM(20),75μM (20), different doses of puerarin（Pue）5mg.kg-1group (20),15mg.kg-1group (20),45mg.kg-1group (20),30mg.kg-1group (20),100mg.kg-1group (30),300mg.kg-1group (30).We made model with Coxsackie B3virus (CVB3) isolates by the method of the VMCclassical. Experimental day0,4,7,14,28, we blooded, killed mice and specimens frommyocardial tissue for subsequent experiments. Myocardial cell apoptosis of mice wasdetected with flow cytometry in each group, the application of the Real-Time PCR assayNrf2mRNA, HO-1mRNA, Fas mRNA and TGF-β1mRNA level of transcription and detected protein expression of Nrf2, HO-1, Fas and TGF-β1by Western blot.
We found that Nrf2mRNA and Nrf2protein expression increased with concentration of CPDT (Nrf2activator) and Pue dose increase in each group, showed a concentration or dose-dependent mannerwithin a certain range. Given large doses of Pue (≥100mg.kg-1), a dose-dependentrelationship is broken, Nrf2showing persistently elevated or no reduced state，that HO-1mRNA and protein expression was significantly increased in CPDT and Pue groups, HO-1and Nrf2were positively correlated. Within a certain range （≤45mg.kg-1）, HO-1transcription and protein expression showed a concentration or dose-dependent manner.Given large doses of Pue (≥100mg.kg-1), a dose-dependent relationship was broken, that thenumber of apoptotic cells was decrease in CPDT and Pue group from the cells, mRNA andprotein levels. Nrf2and Fas was negatively correlated. Compared Pue100mg.kg-1groupand Pue300mg·kg-1with VMC group, it showed no significant difference (P＞0.05),Which suggested therapeutic effect of the drug was not increase accordingly with the doseincreasing, that TGF-beta1mRNA and protein expression decreased in a certainconcentration or dose gradient in CPDT and Pue groups. Nrf2and TGF-beta1was negativelycorrelated. When Pue dose increased to a certain extent (≥100mg.kg-1), TGF-beta1expression did not fall but rise. We observed that high-dose Pue does not increase the role ofdrug treatment, but there is a clear diarrhea in mice, significantly increased mortality in mice,CK-MB level was significantly higher, myocardial pathological changes serious. Nrf2, HO-1,Fas, TGF-beta1mRNA and protein expression levels were change, Nrf2and HO-1, Nrf2andFas, Nrf2and TGF-beta1was no correlation.
Therefore, we concluded that Nrf2expression was elevated in VMC mice, and involvedin the occurrence and development of the VMC. Nrf2had effects of antioxidant, inhibittingmyocardial apoptosis and myocardial fibrosis in the VMC. Puerarin may be antioxidativedamage, anti-cardiomyocyte apoptosis and anti-myocardial fibrosis through activating Nrf2in VMC. But It may be has other ways to play these role at the same time. Large dosepuerarin increased adverse drug reactions of diarrhea.
引文
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