摘要
背景:肥厚型心肌病(Hypertrophic Cardiomyopathy, HCM)是一类具有不同表型的异质性疾病,可由多种基因突变引起,其发病率为1:500,中国至少有200万HCM病人被确诊,HCM是引起青年运动员猝死的主要因素之一。HCM的病理学特点为左心室肥厚、心肌细胞肥大,排列紊乱伴明显间质增殖。典型的心肌肥厚和纤维化造成心肌重构,但介导其心肌重构的关键机制仍然不清,引起HCM病人发生心电重构从而诱发猝死的机制一直没有阐明,HCM的心肌重构与心电重构间的关系也不是十分明确。
约60%HCM病人有遗传和家族背景,HCM是心脏疾病中第一个被确认为与基因遗传相关的疾病。自首次报告肌球蛋白重链基因变异引起HCM以来,至少有20个基因,400个以上的DNA变异被报道与HCM发病相关,其中13个属心肌收缩肌小节蛋白。心脏肌钙蛋白I(cardiac troponin I,cTnI)由210个氨基酸组成,是调节心肌细胞收缩和舒张功能的重要抑制因子。cTnI磷酸化是心肌最重要的转录后蛋白修饰方式之一。cTnI磷酸化后,其对钙离子敏感性降低,降低心肌收缩。已有研究表明cTnI丝氨酸(serine)位点磷酸化与HCM发病相关;cTnI基因位点突变引发HCM,表现为典型心室重构。但cTnI突变导致心肌重构、心电重构的机制仍然有待进一步研究。
本课题组在开展苏皖地区HCM人群基因分型研究后,发现了一汉族人HCM家系先症者的心肌肌钙蛋白I(cTnI)第145位变异-cTnI R145W(小鼠为cTnI R146W),它可能是HCM致病基因之一。将cTnI R145W克隆构建和组装入腺病毒载体,干预离体分离培养的大鼠心肌细胞能使大鼠心肌细胞L型钙通道电流峰值明显降低,而胞浆内钙及咖啡因诱导肌浆网钙释放并未明显改变。细胞内钙又是心肌细胞重构的信号通路的重要介导因素,同时还关系着心肌细胞的心电稳定性。因此,研究cTnI R145W突变能否造成心脏重构,探讨其潜在机制将为阐述cTnI R145W和HCM发生、发展的关系,研究其发病的临床特点,阐明其发病关键机制提供一定的依据。
目的:
1)通过显微注射法建立cTnIR146W杂合转基因小鼠(cTnIR146W+/-小鼠)模型,并从基因水平、蛋白水平、组织功能学水平验证该转基因模型。
2)探讨cTnIR146W突变对小鼠心脏形态、结构和功能的影响,研究其可能的分子机制,为下一步治疗靶点的发现提供研究基础。
3)研究运动负荷对cTnIR146W+/-小鼠心脏形态和功能的影响,观察cTnIR146W+/-小鼠的运动耐受性并初步探讨其机制。
内容与方法:
1.将cTnIR146W基因插入α-MHC启动子下游,构建转基因表达载体,通过显微注射法建立cTnIR146W +/-小鼠模型,得到第一代携带突变基因小鼠后,采用与C57BL/6J回交法对转基因小鼠进行传代,并采用PCR方法筛选基因阳性小鼠。
2.建立并优化超声心动图评定小鼠心脏结构和功能的方法和检测参数,利用超声心动图对不同年龄组的cTnIR146W +/-小鼠进行心脏结构和功能的无创性检测,探讨超声心动图作为转基因动物模型初步筛选的无创检查手段的可行性。
3.提取cTnIR146W +/-小鼠心肌蛋白和RNA, RT-PCR、基因测序法验证突变基因mRNA水平表达,Western blot法检测cTnIR146W +/-小鼠总cTnI、cTnI磷酸化水平及cTnIR146W突变蛋白表达水平。
4.应用光学显微镜、电子显微镜观察cTnIR146W +/-小鼠心脏的病理改变,验证心肌肥厚和纤维化重构程度。Western blot和RT-PCR法验证心肌肥厚相关下游蛋白心房利钠肽(atrial natriuretic peptide ,ANF)、脑钠素(brain natriuretic peptide ,BNP)、β-肌球蛋白重链(β-myosin heavy chain,β-MHC)的表达。
5. Western blot和RT-PCR法观察心肌肥厚相关信号通路蛋白钙调神经磷酸酶(calcineurin)、calsarcin-1、糖原合成酶激酶-3β(glycogen synthasekinase-3β,GSK-3β)、AKT、心肌肌浆网Ca2+-ATP酶(SERCA2)、磷酸受钙蛋白(Phospholamban , PLB)等蛋白表达的改变,测定cTnIR146W +/-小鼠心肌组织calcineurin的活性,并采用ELISA法测定细胞核激活T细胞核因子(NFAT c1)含量,探讨诱导cTnIR146W +/-小鼠发生心脏肥厚的主要介导通路及其相关机制。
6. Western blot、RT-PCR、免疫组织化学法观察心肌骨膜素(Periostin)、转化生长因子-β(transforming growth factor,TGF-β)表达,验证其与心脏的纤维化的关系
7.对2月龄、8月龄cTnIR146W +/-小鼠进行游泳负荷干预,观察其运动耐受性。
8.采用超声心动图法比较运动组、静息组及运动前后cTnIR146W +/-小鼠心脏结构和功能,探讨运动对cTnIR146W +/-小鼠心脏结构、功能的影响。
9.光学显微镜、电子显微镜观察运动组、静息组及运动前后cTnIR146W +/-小鼠心脏的病理改变,探讨运动对cTnIR146W +/-小鼠心肌重构的影响。
10. Western blot和RT-PCR法检测运动组、静息组及运动前后cTnIR146W +/-小鼠心肌组织中Periostin表达,探讨cTnIR146W转基因小鼠运动耐受性降低的可能机制。
11.统计学方法:数据均测量以平均数加减标准差( x±s)表示。组间差异采用独立样本t检验、单因素方差分析和χ2检验(SPSS 13.0)分析,P<0.05有统计学意义。
1.显微注射法建立cTnIR146W +/-小鼠模型,得到第一代携带突变基因小鼠后,采用与C57BL/6J回交法对cTnIR146W +/-小鼠进行传代,并采用PCR方法筛选基因阳性小鼠,现已传至第八代,基因型阳性占出生鼠50%,最大年龄鼠已达2周岁。
2.建立并优化超声心动图评定小鼠心脏结构和功能的方法和检测参数,发现超声心动图可作为cTnIR146W +/-动物模型初步筛选的无创性检查手段。与cTnIR146W-/-小鼠相比,各年龄组cTnIR146W+/-小鼠左房内径( left atrial dimension,LAD,P<0.05)均显著增大;8月龄及以上组cTnIR146W +/-小鼠室间隔厚度增加(interventricular septum dimension,IVSd,P < 0.05),室间隔厚度与左室后壁比值增大(IVSd/ left ventricular posterior wall dimension,LVSd/LVPWP<0.05);12月龄及以上组左心室收缩末期内径增大(left ventricular end-systolic dimension,LVDs,P<0.01),左室收缩末期容积增大(end-systolic volume,ESV,P<0.05),射血分数、短轴缩短率下降(Ejection fraction,EF,Fractional shortening ,FS,P< 0.01),组织多普勒显示二尖瓣前叶、后叶瓣环收缩期峰值速度(Systolic maximal velocity ,S峰)速度减低(P<0.05),二尖瓣瓣口的舒张早期血流速度E峰峰值流速显著降低,而舒张晚期血流速度A峰峰值流速基本维持不变,从而导致cTnIR146W +/-小鼠E/A显著降低(P<0.05)。
3.提取cTnIR146W +/-小鼠RNA,RT-PCR扩增cTnI的cDNA,经TAKARA公司测序证实cTnIR146W基因被成功构建入cTnIR146W+/-小鼠;Western blot法检测发现cTnIR146W +/-小鼠表达cTnIR146W突变蛋白,其总cTnI表达水平显著增高(P<0.05)、但磷酸化cTnI表达水平显著性降低,磷酸化cTnI和总cTnI比值明显降低(P<0.05)。
4.在病理组织学上,肥厚型心肌病特点为左心室肥厚、心肌细胞肥大,排列紊乱伴明显间质增殖。采用光学显微镜、电子显微镜观察cTnIR146W +/-小鼠心脏的病理改变,发现cTnIR146W +/-小鼠首先发生心肌细胞核增生,随着月龄的增大继而出现心肌细胞数量减少、排列紊乱、心肌细胞间出现纤维增生并日益加重。采用RT-PCR法发现cTnIR146W +/-小鼠心肌肥厚相关下游蛋白ANF、BNP、β-MHC的mRNA表达水平明显增高(P<0.05),β-MHC/α-MHC比值显著增高(P<0.05)。
5. Western blot和RT-PCR法观察心肌肥厚相关信号通路蛋白,发现cTnIR146W +/-小鼠calsarcin-1表达明显降低(P<0.05),calcineurin活性增高(P<0.05),GSK-3β及Akt磷酸化水平无明显改变,测定cTnIR146W +/-小鼠心肌核NFATc1量,发现cTnIR146W +/-小鼠核NFATc1明显增高(P<0.05)。
6. 8月龄及以上组的cTnIR146W +/-小鼠心肌Periostin、TGF-β表达明显增高(P<0.05),Periostin为间质表达。
7.运动负荷中,8月龄cTnIR146W +/-小鼠的死亡率为50%,8月龄cTnIR146W -/-小鼠的死亡率为17.4%(4/24);χ2结果显示8月龄cTnIR146W +/-小鼠的死亡率明显增高(P<0.01)。2月龄cTnIR146W +/-小鼠的死亡率为39.3%,2月龄cTnIR146W -/-小鼠的死亡率为25%;χ2结果显示2月龄cTnIR146W +/-小鼠的死亡率与cTnIR146W -/-小鼠比较无显著差异,但呈增加趋势。
8. 1)对于2月龄cTnI R146W -/-小鼠,运动后小鼠心脏舒张功能较静息组轻度增高。2)对于2月龄cTnI R146W +/-小鼠,运动负荷导致cTnI R146W +/-小鼠心腔明显增大,心脏收缩、舒张功能减退。3)运动前,2月龄cTnI R146W +/-小鼠和cTnI R146W -/-小鼠间心脏结构和功能并无显著性差异;运动后,和cTnI R146W -/-小鼠相比,cTnI R146W +/-小鼠心腔明显扩大,心脏收缩功能、舒张功能减退。4)运动前,与8月龄cTnI R146W -/-小鼠相比,8月龄cTnI R146W +/-小鼠心腔明显扩大,IVS/LVPW比值显著增高,并且伴有明显的收缩功能、舒张功能减退;运动后,与8月龄cTnI R146W -/-小鼠相比,cTnI R146W +/-小鼠心腔扩大,心脏收缩功能、舒张功能减退没有明显的好转。5)运动导致8月龄cTnI R146W -/-小鼠心脏舒张功能轻度增高(Aa增大); 6)对于8月龄cTnIR146W +/-小鼠,运动负荷后cTnI R146W +/-小鼠心腔仍然明显增大,心脏收缩、舒张功能减退,但和静息组8月龄cTnI R146W +/-小鼠相比,并无显著性差异。
9.运动负荷后,cTnI R146W +/-小鼠游泳组心肌间质增生加重,部分心肌可疑断裂,出现线粒体肿胀,肌丝溶解现象。
10.运动负荷后,cTnI R146W +/-小鼠心肌肥厚相关下游蛋白ANF、BNP、β-MHC的mRNA表达水平明显增高。
11.超声心动图显示,8月龄猝死组cTnI R146W +/-小鼠运动前ESV、LVDs明显低于存活cTnI R146W +/-小鼠,EF、Ea、Ea/Aa明显高于存活cTnI R146W +/-小鼠。2月龄运动前超声心动图显示,猝死组cTnI R146W +/-小鼠和存活组cTnI R146W +/-小鼠间无显著性差异。但猝死组小鼠心脏纤维化及periostin表达明显高于存活组。
结论与讨论:
1.通过基因水平、蛋白水平验证,本课题组已成功建立cTnI R146W +/-小鼠,并已传代至第八代。
2.超声心动图可以做为无创筛查cTnI R146W +/-小鼠的手段。但其对验证该转基因小鼠的心肌肥厚程度并不敏感,低龄组转基因小鼠并不存在明显的心肌肥厚。cTnI R146W +/-小鼠心肌重构的程度和年龄相关,出现典型的病理性心肌肥厚、间质纤维化并伴有明显的心功能改变。
3. cTnI R146W +/-小鼠的心肌肥厚可能由Calcineurin-NFAT通路介导。cTnI R146W +/-小鼠心脏TGF-β表达水平增高伴有periostin表达水平增高,提示TGF-β可能刺激了periostin的表达,介导了心脏纤维化重构。
4. cTnI R146W +/-小鼠运动猝死率明显增高,运动负荷有益于改善cTnI R146W -/-小鼠心脏功能,但却不能逆转甚至加重了cTnI R146W +/-小鼠的心功能紊乱。
5.猝死组cTnI R146W +/-小鼠心脏纤维化程度显著高于存活组cTnI R146W +/-小鼠,伴随periostin表达上调,但是运动前超声心动图显示猝死组心功能明显好于存活组,提示cTnI R146W +/-小鼠运动猝死可能与其心电紊乱更加相关。
Backgroud:
Hypertrophic cardiomyopathy ( HCM ) is caused by a variety of gene mutation with different phenotypic heterogeneity, the incidence rate of HCM is 1:500. HCM is the most common reason of sudden death. Left ventricular hypertrophy, interstitial fibrosis are the typical changes in histopathology of HCM. But the key mechanism of cardiac remodeling is still unclear. The relationship between cardiac remodeling and electrical remodeling has not been clarified till now. HCM is the first identified hereditary cardiovascular diseases. Since the initial report revealed that myosin heavy chain gene mutation was associated with HCM, at least 20 genes, more than 400 mutatons were found to be related with HCM. Cardiac Troponin I(cTnI) is an important component of troponin complex, which was proved to be a regulative unit of cardiomyocyte. Phosphorylation is the most important post-transcriptional modification of cTnI. Phosphorylated cTnI can reduce the susceptibility of calcium, decreased cardiac contractility. Other studies confirmed that cTnI mutation in different position would involve in develop HCM in mice and patients. However the mechanism of myocardial and cardiac electrical remodeling, of cTnI mutation-induced HCM remain to be further studied.
Through genetic screening of patients with HCM in the boad area of Jiangsu and Anhwei Province, we discoverd a cTnI mutation- cTnI R145W (R146W in mice ). To evaluate the effect of this mutation on cardiomyocyte, we transfected the cTnIR145W into cardiomyocyte isolated from rat heart in vitro. L-type calcium channel current peak decreased. However, the cytosolic calcium and caffeine-induced sarcoplasmic reticulum calcium release did not change significantly in rat myocardial cells isolated from rat transtected with cTnI R145W. The data in vitro research suggested that cTnI R145W mutation did reduce the current peak of L-type calcium channel. Intracellular calcium is a vital mediator of cardiac remodeling and cardiomyocyte stability. Therefore, it is necessary to clarify the effect of cTnI R145W mutation on heart remodeling in vivo.?
The emergence of transgenic animal promotes the progress of studies in HCM. The transgenic models of HCM were designed to get further understanding of the pathogenesis of HCM.
Objective:
1. Construct a transgenic model of HCM overexpressing cTnI R146W, observe the pathological change of this animal, and clarify whether this missence mutation is associated with HCM. Using echocardiography to measure the cardiac structure and function, to find a useful method to evaluate the diastolic function of transgenic mice.
2. Elucidate the signaling pathway involving in heart remodeling of cTnI R146W +/- mice.
3. Observe the exercise tolerance of cTnI R146W +/- mice, evaluate the cardiac structure, function, myocardial remodeling of cTnI R146W +/- mice, and investigate the potential mechanism. Materials and methods
1. CTnI R146W mutant cDNA was inserted into downstream ofα-MHC promoter to construct a expression vector of cTnI R146W. By the method of micro-injection, we established cTnI R146W transgenic mice. The first generation of transgenic mice carrying mutant gene were detected by PCR. Then we bred transgenic mice with C57BL/6J, and screened cTnI R146W +/- mice by PCR.
2. To establish and optimize the parameters of echocardiography in assessing the cardiac structure and function in transgenice mice. Using echocardiography to evaluate the cardiac structure and function in different age. Discuss the feasibility of echocardiography as a non-invasive method to screen the transgenic animal with typical phenotype.
3. To optimize protein extraction and purification methods. Verify the mRNA expression level of cTnI R146W by RT-PCR and gene sequencing. Western Blot was used to detect the expression of cTnI R146W in heart. We also measured the phosphorylation of cTnI in cTnI R146W +/- mice to evaluate the modification level of this transgenic mice.
4. Using optical microscope to observe pathological changes of cTnI R146W +/- mice.Western and RT-PCR were used to verify the mRNA expression level of markers of cardiac hypertrophy, such as ANF, BNP,β-MHC.
5. Cardiac hypertrophy-related signaling pathway protein, such as calcineurin, calsarcin-1, GSK-3β, AKT, SERCA2, PLB were detected by Western blot and RT-PCR. We also assessed the activity of calcineurin in cTnI R146W +/- mice, in order to elucidate potential mechanisms involving in the cardiac remodeling in cTnI R146W +/- mice.
6. To find the potential mechanisms of fibrosis in this model, we used Western blot, RT-PCR, immunohistochemistry to detect the expression of periostin and TGF-βin heart.
7. Exercise load was used in this investigation to observe the exercise tolerance of cTnI R146W +/- mice of different age.
8. Echocardiography was used to compare the cardiac structure and function of cTnI R146W +/- mice and cTnI R146W -/- mice before and after exercise.
9. Optical microscope, electron microscope were applied to measure the pathological changes of cTnI R146W +/- mice and cTnI R146W -/- mice before and after exercise.
10. Western blot and RT-PCR were used to verify the mRNA expression level of markers of cardiac hypertrophy in cTnI R146W +/- mice and cTnI R146W -/- mice before and after exercise,such as ANF, BNP,β-MHC.
11. Western blot was used to detect the expression of periostin in cTnI R146W +/- mice and cTnI R146W -/- mice before and after exercise. The possible reasons for sudden death of cTnI R146W +/- mice were investigated by comparing the cardiac structure and function and the expression of periostin dying during exercise with survival ones.
12. Statistics: All data are presented as mean±SD. Quantity One 4.5.2 Quantitation software (Bio-Rad, USA) were used to perform semi-quantification. The independent samples T test or One– way ANOVA were used to analyze differences and statistical tests were performed with the use of SPSS 13.0 statistical software. Statistical significance was accepted at P<0.05. Results:
1. CTnI R146W mutant cDNA was successfully inserted into downstream ofα-MHC promoter. Through micro-injection. we established cTnI R146W transgenic mice, the first generation of transgenic mice carrying mutant gene were detected by PCR. The genotype positive mice accounted for 50%, the eldest mice was 2 years old.
2. Echocardiography can be used as a non-invasive method to screen the transgenic animal with typical phenotype. Echocardiography can help us to measure the cardiac structure and function, evaluate the systolic and diastolic function of mice. The results showed that compared with cTnI R146W -/- mice, LAD increased significantly in cTnI R146W +/- mice (P<0.05 ); IVSd increased from 8 month(P<0.05); LVDs, IVS, IVS/LVPW increased obviosly (P<0.05) while EF、FS decreased significantly in 12-14 month mice(P <0.01). TDI (Tissue Doppler imaging) showed that transmitral late filling velocity (A peak) was significant higher in 12-14 month old cTnI R146W +/- mice(P<0.05), while transmitral early filling velocity (E peak) was similar with 12-14 month old cTnI R146W -/- mice. Meanwhile, the peak speed of mitral anterior leaflet, posterior lobe ring(S) reduced in 12-14 month old cTnI R146W +/- mice(P<0.05).
3. The mRNA expression of cTnI R146W were determined by Northern blot、RT-PCR and gene sequencing. The protein expression of cTnI R146W were proved by Western blot. The total expression of cTnI in cTnI R146W +/- mice was significant higher than cTnI R146W -/- mice(P<0.05), while the phosphorylation of cTnI decreased significantly ( P<0.05), resulting in a obvious decrease of the ratio of phos-cTnI to cTnI( P<0.05).
4. Pathological changes such as myocardial cell proliferation, cardiac hypertrophy, and interstitial fibrosis were observed by optical microscope in cTnI R146W +/- mice. Markers of cardiac hypertrophy, such as ANF, BNP,β-MHC increased significantly in cTnI R146W +/- mice(P<0.05).
5. The expression of calsarcin-1 in cTnI R146W +/- mice was significant higher than that of cTnI R146W -/- mice(P<0.01), while other cardiac hypertrophy-related signaling pathway protein, such as calcineurin, GSK-3β, AKT, SERCA2 did not changed. The mRNA expression of PLB reduced obviously by RT-PCR(P<0.05). Meanwhile, the calcineurin activity of cTnI R146W +/- mice increased significantly(P<0.01).
6. The mRNA expression of TGF-βelvated obviously by RT-PCR compared with cTnI R146W -/- mice. However, The expression of periostin in cTnI R146W +/- mice was significant higher than cTnI R146W -/- mice(P<0.05) from 8 month.
7. During swimming, the mortality of 8 month old cTnI R146W +/- mice and cTnI R146W -/- mice was 50% and 17.4%, respectively. While the mortality of 2 month old cTnI R146W +/- mice and cTnI R146W -/- mice was 39.3% and 25%, respectively. The results showed that the exercise tolerance of 8 month old cTnI R146W +/- mice reduced significantly. The exercise tolerance of 2 month old cTnI R146W +/- mice did not have any significant difference.
8. By the using of echocardiography, we found LAD, LVDs, ESV, A increased significantly while FS, EF, S, E/A, Ea decreased in 2 month old cTnI R146W +/- mice after swim compared with sedentary ones (P<0.05). However, only LAD elevated in 8 month old cTnI R146W +/- mice after swim compared with sedentary ones(P<0.05). Only LAD elevated in 2 month old sedentary cTnI R146W +/- mice compared with sedentary cTnI R146W -/- mice (P<0.05). However, LVDd, A, Aa increased significantly while FS, EF, E/A, Ea, Ea/Aa decreased in 8 month old sedentary cTnI R146W +/- mice compared with sedentary cTnI R146W -/- mice (P<0.05). LVDd, ESV, ESV, A increased significantly while E/A, Ea decreased in 2 month old cTnI R146W +/- mice after swim compared with 2 month old cTnI R146W -/- mice (P<0.05). However, LVDd, A increased significantly while E/A, Ea, EF, FS, Ea/Aa decreased in 8 month old cTnI R146W +/- mice after swim compared with 8 month old cTnI R146W -/- mice (P<0.05).
9. After swimming, pathological changes such as myocardial cell proliferation, cardiac hypertrophy, and interstitial fibrosis aggravated in cTnI R146W +/- mice compared with cTnI R146W -/- mice.
10. The mRNA expression of cardiac hypertrophy markers, such as ANF, BNP,β-MHC elevated significantly in cTnI R146W +/- mice compared with cTnI R146W -/- mice.
11. By Comparing the cardiac structure and function between cTnI R146W +/- mice dying during exercise and the survival ones, we found a significant increase of systolic and diastolic function in dead ones. The extent of fibrosis of cTnI R146W +/- mice dying during exercise was higher than the survival ones accompany with increasing expression of periostin. Conclusions:
1. Through micro-injection, we had successfully established cTnI R146W transgenic mice.
2. Echocardiography can be used as a non-invasive method to screen the transgenic animal with typical phenotype. cTnI R146W +/- mice had typical pathological cardiac remodeling and heart dysfunction, especially in the elder ones.
3. The activity of calcineurin-NFAT signaling pathway may be the most important mechanism involving in pathological cardiac hypertrophy. While the higer expression of TGF-βmight stimulate the expression of periostin, and influence the fibrosis of heart.
4. The mortality of cTnI R146W +/- mice during swim increased significantly, indicate a reduced exercise tolerance in cTnI R146W +/- mice. Exercise can enhance the heart function of cTnI R146W -/- mice. By contrast, exercise aggravate the heart function and cardiac remodeling in cTnI R146W +/- mice.
5. The extent of fibrosis in cTnI R146W +/- mice dying during exercise was higher than the survival ones accompanied with increasing expression of periostin and better heart function before swim, indicating that the high incidence of sudden death in cTnI R146W +/- mice during exercise may result from electrical instability rather than heart dysfunction.
引文
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