摘要
第一部分人参皂甙Rb1对cTnTR141W转基因扩张型心肌病小鼠模型的治疗作用及机理研究
背景近年来心血管领域的一个研究热点是心血管重构的药物干预。已发现多种西药及中药有效成分,能够逆转高血压、心梗等导致的心脏重构,尤其是左心室肥大(left ventricular hypertrophy, LVH)的发生和发展。然而却缺乏能够有效逆转扩张型心肌病(dilated cardiomyopathy, DCM)的心脏扩张及心功能衰竭的药物。本文从对心血管疾病有较好疗效的中药单体中挑选出11种,利用本所遗传中心建立的cTnTR141W转基因DCM小鼠模型,筛选得到可改善DCM心脏功能及重构的药物两种,分别是Rb1(Ginsenoside-Rb1)和TMPP (Tetramethylpyrazine phosphate),我们从多个层次研究其药理作用并进行机制的研究。方法对2月龄的cTnTR141W阳性鼠进行心脏超声检测,计算左心室收缩期内径(leftventricular internal diameter at end-systole, LVIDs)的平均值和95%的可信区间。我们将95%的可信区间的上限作为心脏扩张的标准,排除部分表型不显著的cTnTR141W阳性鼠。其余的阳性鼠被随机分为模型组和人参皂甙Rb1治疗组(70 mg/kg/d)。用相同年龄的阴性鼠作为对照组。分组后每个月进行一次超声。连续给药7个月。在长期给药的过程中以及给药终点,观察各给药组与模型组心功能各项指标的变化。进行Kaplan-Meier生存分析。计算心重指数。HE染色和Masson染色观察心肌细胞变化及间质变化。透射电镜分析心肌超微结构。RT-PCR检测心肌粘附蛋白Cx40、Cx43、E-cad、N-cad、P-cad、itga8和itgb1bp3的表达。免疫荧光激光共聚焦观察心肌粘附分子Itga8的表达与分布。Western blot检测心脏HB-EGF, pSTAT3, STAT3表达水平。结果Rb1长期给药能显著改善该模型的心功能和心脏几何构型,将死亡率降低50%。Rb1治疗组心重指数降低11.3%(P<0.05)。光镜观察显示Rb1能减轻心肌细胞排列紊乱以及间质纤维化。透射电镜观察显示Rb1能减轻心肌超微结构的破坏。RT-PCR结果显示,在模型中Cx40表达降低,E-cad、itga8和itgb1bp3表达升高,但在Rb1组中接近正常水平。免疫荧光激光共聚焦结果显示Rb1可降低Itga8的表达量并调节其分布。Western blot结果显示Rb1能够显著降低模型中的HB-EGF及pSTAT3的表达,但tSTAT3的表达在三组无显著差异。结论本研究显示,Rb1与TMPP可作为治疗遗传性DCM的候选药物。Rb1可改善扩张型心肌病模型的心功能,抑制心脏重构,其作用可能部分通过调节粘附蛋白的表达,抑制心肌病发生中的HB-EGF表达及抑制下游信号pSTAT3的激活实现的。
第二部分磷酸川芎嗪对cTnTR141W转基因扩张型心肌病小鼠模型的治疗作用及机理研究
目的利用cTnTR141W转基因扩张型心肌病小鼠模型,研究磷酸川芎嗪(TMPP)对遗传性扩张型心肌病心功能及重构的影响,并对其机制进行研究。
方法将cTnTR141W转基因阳性鼠随机分为模型组和TMPP组(45mg/kg/d),连续给药7个月,取同龄阴性鼠作为对照组。超声检测心脏功能及几何构型。用Kaplan-Meier法进行生存分析。计算心重指数。RT-PCR检测心肌肥厚标志基因的表达。HE染色和Masson染色观察心肌细胞变化及间质变化。透射电镜分析心肌超微结构。Western blot和免疫荧光激光共聚焦观察心肌肌小节蛋白Myotilin和MLC2的表达与分布。RT-PCR检测心肌钙相关信号CaM/CaMKⅡ通路的表达情况。
结果TMPP长期给药能显著改善该模型的心功能和构型,将死亡率降低54%。TMPP显著降低心重指数(P<0.05),并降低心肌肥大标志基因ACTA1、BNP的表达,即减轻了扩心病小鼠的心肌肥厚。光镜观察显示TMPP能减轻心肌细胞排列紊乱以及间质纤维化。透射电镜观察显示Rbl能减轻心肌超微结构的破坏。Western blot及免疫荧光激光共聚焦结果显示,在模型组中,心肌肌小节Z-disc蛋白Myotilin表达升高,收缩蛋白MLC2磷酸化程度降低,给药处理后其表达接近正常水平。RT-PCR结果显示,在模型组中,心肌钙信号通路CaM/CaMKⅡ被激活,TMPP对该信号通路有抑制作用。
结论TMPP可改善扩张型心肌病模型的心功能,抑制心脏重构,其作用可能部分通过抑制钙激活信号通路包括CaM/CaMKⅡ通路而实现的。
第三部分心脏特异表达NOL3转基因小鼠的建立
目的建立心脏特异表达NOL3转基因小鼠,用于研究该基因在心肌病发病中的作用。
方法Western blot检测小鼠NOL3表达谱。构建αMHC-NOL3表达载体,显微注射法建立NOL3转基因小鼠。PCR鉴定转基因鼠的基因型,心脏超声检测转基因及野生型小鼠心脏功能及几何构型。
结果NOL3在1月龄野生型鼠心脏、脑、骨骼肌中的高表达,在心脏中的表达不随年龄而改变。通过转基因小鼠的筛选,得到了3个NOL3转基因品系,其中1个品系心脏NOL3蛋白表达量与野生型鼠相比明显增加。单转NOL3基因的小鼠心脏功能及几何构型与野生型小鼠相比无显著变化。
结论成功建立了心脏特异表达NOL3转基因小鼠,为进一步和心肌病小鼠模型杂交,研究该基因在心肌病发病中的作用提供了工具。
The effects and mechanisms of ginsenoside-Rbl on DCM in the cTnTK141W transgenic mouse
Backgroud The researches of inhibition of cardiac remodeling by drugs have been developed rapidly in recent years. It has been found that many effective components in Chinese herb could prevent the development of cardiac remodeling especially left ventricular hypertrophy, which occurred in hypertension, myocardial infarcion. But the study about the medicinal therapy for DCM was absent. Here, using the cTnTR141W transgenic mouse model of DCM, tetramethylpyrazine phosphate (TMPP) or ginsenoside-Rb1 were screening out from 11 kinds of compounds from Chinese herbs which showed beneficial effect on cardiovascular diseases, as the potential drugs for prevention of cardiac dysfunction and dilation in DCM. We further studied the effects and the possible underlying mechanisms of Rbl on cardiac remodeling of dilated cardiomyopathy in cTnTR141W transgenic mouse.
Methods We performed M-mode echocardiography in aMHC-cTnTR141W transgenic mice at the ages of 2 months, which is considered the predilated stage of DCM. We determined the mean and the 95%confidence interval (CI) of the left ventricular internal diameter at end-systole (LVIDs) in the transgenic mice. We used the upper limit of the 95%CI as the evidence for cardiac dilation and excluded the cTnTR141W mice with no significantly phenotype of DCM. The remainder transgenic mice were randomized to model group or drug group (Rb1,70 mg/Kg/d). Age-matched nontransgenic mice drinking water were used as wild type control. The drug was administered for 7 months. We detected the cardiac function and geometry by echocardiography once 1 month. Histology and transmission electron microscopy were used to assess myocardial organization, myocardial interstitial fibrosis and ultrastructure. The expression of adhesion proteins was detected by RT-PCR. Immunofluorescence was performed to examine localization of Itga8. The expression of HB-EGF, pSTAT3 and STAT3 were detected by western blot.
Results We found that long-term administration of ginsenoside-Rb1 significantly improved cardiac function and reduced mortality by 50%. The HW/BW ratio of Rbl-treated mice was significantly lower than that of placebo mice (11.3%, P< 0.05). Histological analysis showed that Rb1 attenuated the myocardial disarray, decreased the interstitial fibrosis, and ultrastructural abnormality in the cTnTR141W heart. RT-PCR revealed that the expression of Cx40, E-cad, itga8 and itgb 1 bp3 were turned over to nearly normal levels in the Rb1 group, while the decreased expression of Cx40 and the increased expression of E-cad, itga8 and itgb 1 bp3 were detected in the placebo group. Confocal immunofluorescence showed that Rb1 regulated the distribution of Itga8. Western blot analysis indicated that Rb1 treatment significantly downregulated HB-EGF and pSTAT3 expression, which were steadily overexpressed in the placebo mice.
Conclusion We showed that Rb1 and TMPP could be the potential drugs for DCM therapy. These findings revealed that Rb1 could improve cardiac function and inhibit cardiac remodeling of DCM in cTnTR141W transgenic mice, partly through regulating adhesion proteins expression and downregulated the HB-EGF expression and STAT3 activation during development of dilated cardiomyopathy in the cTnTR141W transgenic mice. The effects and mechanisms of tetramethvlpvrazine phosphate on DCM in the cTnTR141w transgenic mouse
Background and purpose:Dilated cardiomyopathy (DCM) is the most common cause of heart failure. Familial DCM (FDCM) may account for 20-48%of DCM, and specific medicines for its treatment are not currently available. Tetramethylpyrazine (TMP) has been shown to provide a substantial cardioprotective effect. In the present study, we used the cTnTR141W transgenic mouse model to test the effect of tetramethylpyrazine phosphate (TMPP) on FDCM.
Experimental approach:We evaluated the effect of TMPP on cardiac function and geometry by M-mode echocardiography once a month after randomization. The cardiac hypertrophic markers were analyzed, the microstructure and ultrastructure of heart were observed, and the expression and localization of structural proteins were detected in the mice aged 6 months. In addition, CaM/CaMK II signaling pathway was investigated as the possible intracellular mechanism.
Key results:TMPP significantly improved cardiac function and decreased mortality of cTnTR141W mice by 54% after 7 months of treatment. The HW/BW ratio, and gene expression of hypertrophic markers (NPPB, ACTA1) in cTnTR141W mice was decreased remarkedly by TMPP treatment. Histologic analysis showed that TMPP reduced myocyte disarray, interstitial fibrosis and ultrastructural abnormality in cTnTR141W mice. Western blot and immunofluorescence analysis indicated that TMPP decreased the expression of sarcomeric protein myotilin while increasing the expression of MLC2 in cTnTR141w mice. RT-PCR revealed an inhibition effect of TMPP on CaM/CaMKⅡsignaling pathway.
Conclusions and implications:TMPP was shown to prevent heart failure and left ventricular remodeling in the cTnTR141W transgenic mouse of DCM, and it mechanism may be related to its inhibition of CaM/CaMK II signaling pathway.
Abbreviations:DCM, dilated cardiomyopathy; FDCM, familial DCM; cTnT, cardiac troponin T; TMPP, Tetramethylpyrazine phosphate; HW/BW, heart weight/body weight; The establishment of heart specific NOL3 gene transgenic mice
Objective To establish nucleolar protein 3 (NOL3) transgenic mice and investigate its effect on the development of cardiomyopathy.
Methods The NOL3 expression in the different tissues and different ages of mice was detected with western blot. Transgenic mice were generated by the method of microinjection. The genotype of transgenic lines was identified by PCR. The cardiac function and geometry were detected by echocardiography.
Results The western blot analysis showed that NOL3 was expressed in quite higher levels in the tissues of heart, muscle and brain than in other tissues. The NOL3 expression in the heart maintained a high level from newborn to adult. Three founders of hearts specific a-MHC-NOL3 transgenic mice were established and one high-level expression line was identified. The transgenic gene itself did not affect the cardiac function and geometry compared with the wild type mice.
Conclusion The transgenic mice with cardiac-specific expression of the human NOL3 gene were established successfully and it can be used to cross with the DCM and HCM models to investigate the function of NOL3 gene on the development of cardiomyopathy.
引文
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