中国汉族致心律失常性右室心肌病家系桥粒基因筛查及DSG2~(F531C)突变的致病机制研究
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摘要
第一部分中国汉族家系致心律失常性右室心肌病桥粒基因的筛查
背景：致心律失常性右室心肌病(arrhythmogenic right ventricular cardiomyopathy, ARVC)是青壮年和运动员猝死的常见原因之一,其特征性病理改变为心肌进行性地被纤维或纤维脂肪组织替代。已证实50%以上的ARVC患者携带有桥粒蛋白基因突变。然而,中国汉族家系ARVC患者五个桥粒基因筛查尚未见报道。
目的：本研究的目的是筛查一个中国汉族ARVC家系的致病基因,并分析这一家系的临床特征。
方法：采集一个大的ARVC家系(DS家系),共5代32个成员。对DS家系同意进入本研究的亲属进行病史采集、标准十二导联心电图记录、24小时动态心电图监测、超声心动图检查和血浆采集。依据家族性ARVC的诊断标准确定该家系的患病成员。对该家系成员进行PKP2、DSP、JUP、DSG2和DSC2桥粒基因突变筛查,并以200名健康志愿者为对照,分析核苷酸变异的出现频率。基因核苷酸变异在人群中出现频率<1%者被认为是基因突变,≥1%者被认为是单核苷酸多态性。同时与西班牙ARVC基因突变数据库(http://www.arvcdatabase.info/)和美国遗传性心律失常数据库(http://www.fsm.it/cardmoc/)中收录的桥粒基因突变比较,确定新的突变位点。
结果：共有13名家系成员入选本研究,其中7例被确诊为ARVC。DS家系的平均发病年龄在50.56.38岁,所有患者均有胸闷和心悸,其中先证者的大姐在50岁发生猝死。随访期间,先证者的二姐左心室亦受累,表现为双心室增大、LVEF值由原先的63.1%下降至54%。先证者的二弟虽然没有出现临床心力衰竭的表现,但超声提示心功能下降,EF值为43.5%。所有患者的胸前导联T波广泛倒置,起源于右心室的频发室性期前收缩,4例同时合并左束支传导阻滞型室速。除先证者小妹外,其余6例患者体表心电图V1-3导联终末激动时间延长[90.5±18.8(65-120)ms],且在QRS波之后ST段起始部出现典型的Epsilon波。先证者的大弟弟在2010年随访时发现与4年前的心电图比较有动态改变,V1-5导联出现典型的Epsilon波。对DS家系13个成员的外周血5个桥粒基因外显子测序,发现编码桥粒蛋白DSG2基因发生变异c.1592T>G,导致第531位的半胱氨酸被苯丙氨酸替代。DSG2c.1592T>G变异在正常人的检出率为1/400。生物信息学分析发现,该突变位点所在的氨基酸从低等生物、脊椎动物甚至于DSG2所在的钙粘素蛋白家族中的其他成员都是十分保守的。所有患者均为纯合子,杂合子携带者不患病。
结论：DS家系ARVC患者均合并典型的心电图改变,超声心动图的动态演变提示ARVC是一种进展性心肌病。该家系的致病基因为DSG2,具有较高的外显率,有可能以常染色体隐性遗传方式传递。DSG2c.1592T>G突变很可能是一个致病突变。
第二部分转录组学和分子生物学研究揭示DSG2基因致ARVC机制
背景：DSG2是一种单次跨膜桥粒钙粘糖蛋白,其功能区域的结构和生物化学相互作用的研究已经证实,DSG2蛋白在细胞分化、增值、凋亡和迁移过程中扮演了重要的角色。有研究报道,致心律失常性右室心肌病患者约10%携带有DSG2基因突变。我们先前的研究发现,DSG2沉默后,纤维化指标(Collal, Col1a2, Co13al)、脂肪化指标(Adiponectin, PPAR-y, C/EBP-a)以及细胞凋亡显著增加,类似于人类ARVC的分子改变。然而,DSG2基因致ARVC的分子机制目前并不清楚。
目的：以心房肿瘤细胞系HL-1细胞为研究对象,分析DSG2基因沉默后转录水平改变,为ARVC机制研究提供新的思路。
方法：合成特异性针对DSG2基因编码区的干扰序列,构建pGPU6/GFP/Neo-ShDSG2(ShDSG2)真核表达质粒转染HL-1细胞,G418筛选获得稳定转染的细胞株。用RT-PCR和Western blot检测DSG2在mRNA和蛋白水平表达变化,筛选出沉默效率最佳的细胞株。应用NimbleGen mRNA真核生物基因表达谱芯片寻找沉默DSG2基因后差异的表达基因。通过GO功能注释和KEGG在线数据库筛查新的靶点和信号通路。
结果：我们筛选出沉默效率最高的HL-1细胞株(ShDsg2-273细胞系,DSG2基因在mRNA水平下降71.67%,蛋白水平下降51.72%,P<0.05),分析发现一共有2282个差异表达基因,改变一致的基因有2224个。其中,上调差异表达基因820个,下调差异表达基因1404个。通过GO数据库对基因功能注释并进行基因功能聚类分析发现,这些差异表达基因主要参与：心脏的发育,心肌收缩,肌丝组装和滑行速度,肌原纤维的组装,心肌细胞形态,信号转导,转录调节,细胞凋亡、增殖、分化和发育,免疫应答,炎症反应,离子通道运输过程,脂肪酸代谢等生物学过程。同时,我们应用在线MAS3.0软件中"KEGG pathway"功能模块进行分析,发现差异基因共富集14个信号通路,包括酪氨酸代谢、MAPK信号通路、细胞间通讯、粘附和紧密连接、钙离子信号通路、脂肪细胞因子通路、调节肌动蛋白骨架、Wnt信号通路和细胞周期等。DSG2表达被抑制后出现心肌结构蛋白、凋亡、纤维化、脂肪化和CX43等的mRNA表达均出现了显著的改变,类似于ARVC的分子改变；多个离子通道相关蛋白,特别是复极化相关的离子通道的基因mRNA表达出现了显著下调。DSG2基因沉默后,PG蛋白表达显著下调,β-catenin入核增多,激活AKT/β-catenin信号通路。
结论：DSG2基因沉默后,转录水平的改变类似于人类ARVC的分子改变。细胞凋亡增加、缝隙连接蛋白Cx43重构以及离子通道蛋白相关蛋白的显著下调共同参与ARVC的发生。
第三部分心脏特异表达DSG2F536C转基因小鼠的建立及表型初步分析
背景：本中心对中国汉族家系ARVC患者基因筛查研究发现一个高度保守的DSG2基因F531C突变。但该突变对DSG2蛋白功能的影响及其可能的致病机制目前并不清楚。
目的：建立心脏特异表达的DSG2F536C转基因小鼠,同时初步分析其心脏结构、功能改变。
方法：把DSG2F536C基因插入a-MHC启动子下游,构建转基因表达载体,显微注射法建立B6CBF1DSG2F536C转基因小鼠,PCR鉴定转基因小鼠的基因型,采用Western Blot鉴定DSG2F536C在心脏组织中的表达,记录转基因小鼠死亡情况。利用心脏超声影像分析其心脏整体功能,同时通过HE和Masson染色观察转基因小鼠心肌病理学改变。
结果：建立了3个表达水平不同的心脏组织特异表达的DSG2F536C转基因小鼠品系和2个DSG2WT转基因小鼠品系。突变型转基因小鼠于6周出现心功能下降,而野生型转基因小鼠心功能和同窝非转基因小鼠相比,无明显异常。其中高表达Line (Tg-FC/H)在出生时,体型均小于同窝非转基因小鼠。Masson染色发现Tg-FC/H小鼠心肌细胞排列正常,但左心室出现局灶性纤维化、心肌细胞体积增大。免疫荧光发现闰盘区域PG蛋白显著下调而beta-catenin代偿性上调。
结论：DSG2F536C转基因小鼠的建立为DSG2突变与心肌病发病机制的关系的研究提供了有价值的疾病动物模型。
Part I:Screening of desmosome genes in a Chinese family with Arrhythmogenic right ventricular cardiomyopathy
Background:Arrhythmogenic right ventricular cardiomyopathy (ARVC), characterized by right ventricular fibrofatty replacement and malignant ventricular arrhythmias, is a common reason to premature death. Mutations in the desmosome-encoding genes have been reported in patients with ARVC. However, there are hardly any genetic studies in Asians. In this study, we aimed to investigate the clinical characteristics, cardiac manifestations and desmosome gene mutations in one extended Chinese ARVC family.
Objectives:The aim of this study was to investigate the phenotype of Chinese ARVC family and to screen the mutations in desmosome-encoding genes in this family.
Methods:The family members were evaluated by12-lead ECG, two-dimensional echocardiography (2-DE) and24-hour Holter. Genomic DNA of subjects in this study was extracted from peripheral whole blood and the mutational analysis of desmosmes was performed using polymerase chain reaction (PCR) and direct sequencing. The DNA sequence variants in this study were searched in the Single-nucleotide Polymorphism (SNP) Database and the Inherited Arrhythmias Database to detect whether the variants had been reported previously. New nonsynonymous sequence variant would be assessed in a population of200ethnically matched normal controls (400allels) to exclude the possibility of SNP.
Results:Thirteen out of32members were recruited for this study, seven of which were diagnosed ARVC. All patients presented with palpitations and chest dyspnea, and the eldest sister of the index case died suddenly at the age of50. The age of onset of symptomatic ARVC was50.5±6.38years. Regional wall motion abnormalities were identified by2-DE in right ventricular free wall in all patients. During follow-up,2-DE revealed biventricular dilation with RV aneurysm in the proband's elder sister. Despite the systolic impairment in proband's younger brother, the NYHA functional class remained II. Twelve-lead ECG demonstrated extended T wave inversion. Except for the youngest sister, all patients presented with Epsilon wave after the QRS complex and the terminal activation delay was90.5±18.8(65-120) ms. The eldest brother had no epsilon waves upon S-ECG, when initially diagnosed ARVC. Four years later, QRS complex was widen and Epsilon waves were detected in precordial leads. In this family, all were homoozygous for the F531C mutation in DSG2, and this mutation was highly conservative in different species.
Conclusion: Mutations in DSG2display a high degree of penetrance. Dynamic changes of ECG and2-DE suggest ARVC is a progressive disease with LV involvement as a prominent feature in this family.
Part Ⅱ:Transcriptome profiling and molecular biological study reveals a major role for DSG2in the pathogenesis of ARVC
Background:Desmoglein-2(DSG2) is transmembrane cell adhesion protein of desmosomes. Mutations of DSG2have been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting that DSG2may play a role in the pathogenesis of ARVC. In our previous study, we found the loss of DSG2recapitulate the molecular changes of ARVC. However, no study has examined the mechanistic contribution of DSG2deficiency to ARVC.
Objectives:The aim of our study is to investigate the loss of DSG2on the apoptosis of HL-1cell and changes of transcriptome profiling.
Methods:A set of DSG2-specific siRNAs were synthesized and cloned into the vectors pGPU6/GFP/Neo. The recombinant plasmids pGPU6/GFP/Neo-ShDSG2(ShDSG2) were transfected into HL-1cells, and the positive cells clones were screened with G418. The suppression effect of DSG2mRNA and protein was measured by RT-PCR and Western blot to select the optimal cell line. NimbleGen mRNA microarray were used to examine differentially expressed genes between normal HL-1cells and DSG2silenced HL-1cells.
Results:Four recombinant ShDSG2plasmids were constructed successfully and transfected into HL-1cells to induce RNAi, and stable cell lines were enstablished. ShDSG2-273group could effectively knockdown the DSG2gene expression in mRNA level (71.67%, P=0.004) and in protein level (51.72%, P<0.001), as compared with the normal HL-1cell line. We found2282differential expressed gene (up-regulated820genes, down-regulated1404genes). Meanwhile, Gene Ontology analysis showed significant alteration of gene functions such as cardiac muscle fiber development, actomyosin structure organization and regulation of heart contraction. Cardiac ion channels composed of potassium and calcium were significantly decreased after DSG downregulation. In addition, KEGG Pathway analysis demonstrated deregulation of many important signaling pathways including Tyrosine metabolism, MAPK signaling pathway and Cell Communication. Moreover, we found that loss of DSG2activated AKT/beta-catenin.
Conclusion:Loss of DSG2in HL-1cell produced broad transcription changes that were similar to human ARVC. The occurrence of apoptosis, remodeling of Cx43and deregulation of ion channels may contribute to the pathogenesis of ARVC.
Part Ⅲ:The estabilishement and analysis the phenotype of cardiac-specific DSG2F536c transgenic mice
Background:In our previous study, we found a highly conservative mutation F531C in DSG2gene associated arrhythmogenic right ventricular cardiomyopathy (ARVC). However, the relationship between this mutation and ARVC is unclear.
Objective:To generate the cardiac-specific DSG2F536C expression transgenic mice and to determine the cardiac functional and morphological changes of the mice.
Methods:The transgenic vector was constructed by inserting the mouse DSG2F536C gene into the downstream of α-MHC promoter. The transgenic mice were created by the method of micro injection. The genotype of the transgenic line was identified by PCR and the expression level of the gene was determined by Western blot. The pathologic changes were analyzed with echocardiography and Masson staining.
Results:Three lines of B6CBF1DSG2F536C and two lines of DSG2WT transgenic mice were established. The high expressed line was smaller than the littermates after birth. The histological examination of Tg-H transgenic mice showed increased size of cardiomyocytes and decreased percent fractional shortening (FS%) compared with the DSG2WTtransgenic mice by echocardiography analysis. Myocardial hypertrophy and fibrosis were observed by histological analysis.
Conclusions The DSG2F536C transgenic mice produce a similar pathological phenotype with the human arrhythmogenic right ventricular cardiomyopathy (ARVC). The transgenic mice could be a useful animal model to explore the mechanisms of mutation in DSG2causing ARVC.
背景：致心律失常性右室心肌病(arrhythmogenic right ventricular cardiomyopathy, ARVC)是青壮年和运动员猝死的常见原因之一,其特征性病理改变为心肌进行性地被纤维或纤维脂肪组织替代。已证实50%以上的ARVC患者携带有桥粒蛋白基因突变。然而,中国汉族家系ARVC患者五个桥粒基因筛查尚未见报道。
目的：本研究的目的是筛查一个中国汉族ARVC家系的致病基因,并分析这一家系的临床特征。
方法：采集一个大的ARVC家系(DS家系),共5代32个成员。对DS家系同意进入本研究的亲属进行病史采集、标准十二导联心电图记录、24小时动态心电图监测、超声心动图检查和血浆采集。依据家族性ARVC的诊断标准确定该家系的患病成员。对该家系成员进行PKP2、DSP、JUP、DSG2和DSC2桥粒基因突变筛查,并以200名健康志愿者为对照,分析核苷酸变异的出现频率。基因核苷酸变异在人群中出现频率<1%者被认为是基因突变,≥1%者被认为是单核苷酸多态性。同时与西班牙ARVC基因突变数据库(http://www.arvcdatabase.info/)和美国遗传性心律失常数据库(http://www.fsm.it/cardmoc/)中收录的桥粒基因突变比较,确定新的突变位点。
结果：共有13名家系成员入选本研究,其中7例被确诊为ARVC。DS家系的平均发病年龄在50.56.38岁,所有患者均有胸闷和心悸,其中先证者的大姐在50岁发生猝死。随访期间,先证者的二姐左心室亦受累,表现为双心室增大、LVEF值由原先的63.1%下降至54%。先证者的二弟虽然没有出现临床心力衰竭的表现,但超声提示心功能下降,EF值为43.5%。所有患者的胸前导联T波广泛倒置,起源于右心室的频发室性期前收缩,4例同时合并左束支传导阻滞型室速。除先证者小妹外,其余6例患者体表心电图V1-3导联终末激动时间延长[90.5±18.8(65-120)ms],且在QRS波之后ST段起始部出现典型的Epsilon波。先证者的大弟弟在2010年随访时发现与4年前的心电图比较有动态改变,V1-5导联出现典型的Epsilon波。对DS家系13个成员的外周血5个桥粒基因外显子测序,发现编码桥粒蛋白DSG2基因发生变异c.1592T>G,导致第531位的半胱氨酸被苯丙氨酸替代。DSG2c.1592T>G变异在正常人的检出率为1/400。生物信息学分析发现,该突变位点所在的氨基酸从低等生物、脊椎动物甚至于DSG2所在的钙粘素蛋白家族中的其他成员都是十分保守的。所有患者均为纯合子,杂合子携带者不患病。
结论：DS家系ARVC患者均合并典型的心电图改变,超声心动图的动态演变提示ARVC是一种进展性心肌病。该家系的致病基因为DSG2,具有较高的外显率,有可能以常染色体隐性遗传方式传递。DSG2c.1592T>G突变很可能是一个致病突变。
第二部分转录组学和分子生物学研究揭示DSG2基因致ARVC机制
背景：DSG2是一种单次跨膜桥粒钙粘糖蛋白,其功能区域的结构和生物化学相互作用的研究已经证实,DSG2蛋白在细胞分化、增值、凋亡和迁移过程中扮演了重要的角色。有研究报道,致心律失常性右室心肌病患者约10%携带有DSG2基因突变。我们先前的研究发现,DSG2沉默后,纤维化指标(Collal, Col1a2, Co13al)、脂肪化指标(Adiponectin, PPAR-y, C/EBP-a)以及细胞凋亡显著增加,类似于人类ARVC的分子改变。然而,DSG2基因致ARVC的分子机制目前并不清楚。
目的：以心房肿瘤细胞系HL-1细胞为研究对象,分析DSG2基因沉默后转录水平改变,为ARVC机制研究提供新的思路。
方法：合成特异性针对DSG2基因编码区的干扰序列,构建pGPU6/GFP/Neo-ShDSG2(ShDSG2)真核表达质粒转染HL-1细胞,G418筛选获得稳定转染的细胞株。用RT-PCR和Western blot检测DSG2在mRNA和蛋白水平表达变化,筛选出沉默效率最佳的细胞株。应用NimbleGen mRNA真核生物基因表达谱芯片寻找沉默DSG2基因后差异的表达基因。通过GO功能注释和KEGG在线数据库筛查新的靶点和信号通路。
结果：我们筛选出沉默效率最高的HL-1细胞株(ShDsg2-273细胞系,DSG2基因在mRNA水平下降71.67%,蛋白水平下降51.72%,P<0.05),分析发现一共有2282个差异表达基因,改变一致的基因有2224个。其中,上调差异表达基因820个,下调差异表达基因1404个。通过GO数据库对基因功能注释并进行基因功能聚类分析发现,这些差异表达基因主要参与：心脏的发育,心肌收缩,肌丝组装和滑行速度,肌原纤维的组装,心肌细胞形态,信号转导,转录调节,细胞凋亡、增殖、分化和发育,免疫应答,炎症反应,离子通道运输过程,脂肪酸代谢等生物学过程。同时,我们应用在线MAS3.0软件中"KEGG pathway"功能模块进行分析,发现差异基因共富集14个信号通路,包括酪氨酸代谢、MAPK信号通路、细胞间通讯、粘附和紧密连接、钙离子信号通路、脂肪细胞因子通路、调节肌动蛋白骨架、Wnt信号通路和细胞周期等。DSG2表达被抑制后出现心肌结构蛋白、凋亡、纤维化、脂肪化和CX43等的mRNA表达均出现了显著的改变,类似于ARVC的分子改变；多个离子通道相关蛋白,特别是复极化相关的离子通道的基因mRNA表达出现了显著下调。DSG2基因沉默后,PG蛋白表达显著下调,β-catenin入核增多,激活AKT/β-catenin信号通路。
结论：DSG2基因沉默后,转录水平的改变类似于人类ARVC的分子改变。细胞凋亡增加、缝隙连接蛋白Cx43重构以及离子通道蛋白相关蛋白的显著下调共同参与ARVC的发生。
第三部分心脏特异表达DSG2F536C转基因小鼠的建立及表型初步分析
背景：本中心对中国汉族家系ARVC患者基因筛查研究发现一个高度保守的DSG2基因F531C突变。但该突变对DSG2蛋白功能的影响及其可能的致病机制目前并不清楚。
目的：建立心脏特异表达的DSG2F536C转基因小鼠,同时初步分析其心脏结构、功能改变。
方法：把DSG2F536C基因插入a-MHC启动子下游,构建转基因表达载体,显微注射法建立B6CBF1DSG2F536C转基因小鼠,PCR鉴定转基因小鼠的基因型,采用Western Blot鉴定DSG2F536C在心脏组织中的表达,记录转基因小鼠死亡情况。利用心脏超声影像分析其心脏整体功能,同时通过HE和Masson染色观察转基因小鼠心肌病理学改变。
结果：建立了3个表达水平不同的心脏组织特异表达的DSG2F536C转基因小鼠品系和2个DSG2WT转基因小鼠品系。突变型转基因小鼠于6周出现心功能下降,而野生型转基因小鼠心功能和同窝非转基因小鼠相比,无明显异常。其中高表达Line (Tg-FC/H)在出生时,体型均小于同窝非转基因小鼠。Masson染色发现Tg-FC/H小鼠心肌细胞排列正常,但左心室出现局灶性纤维化、心肌细胞体积增大。免疫荧光发现闰盘区域PG蛋白显著下调而beta-catenin代偿性上调。
结论：DSG2F536C转基因小鼠的建立为DSG2突变与心肌病发病机制的关系的研究提供了有价值的疾病动物模型。
Part I:Screening of desmosome genes in a Chinese family with Arrhythmogenic right ventricular cardiomyopathy
Background:Arrhythmogenic right ventricular cardiomyopathy (ARVC), characterized by right ventricular fibrofatty replacement and malignant ventricular arrhythmias, is a common reason to premature death. Mutations in the desmosome-encoding genes have been reported in patients with ARVC. However, there are hardly any genetic studies in Asians. In this study, we aimed to investigate the clinical characteristics, cardiac manifestations and desmosome gene mutations in one extended Chinese ARVC family.
Objectives:The aim of this study was to investigate the phenotype of Chinese ARVC family and to screen the mutations in desmosome-encoding genes in this family.
Methods:The family members were evaluated by12-lead ECG, two-dimensional echocardiography (2-DE) and24-hour Holter. Genomic DNA of subjects in this study was extracted from peripheral whole blood and the mutational analysis of desmosmes was performed using polymerase chain reaction (PCR) and direct sequencing. The DNA sequence variants in this study were searched in the Single-nucleotide Polymorphism (SNP) Database and the Inherited Arrhythmias Database to detect whether the variants had been reported previously. New nonsynonymous sequence variant would be assessed in a population of200ethnically matched normal controls (400allels) to exclude the possibility of SNP.
Results:Thirteen out of32members were recruited for this study, seven of which were diagnosed ARVC. All patients presented with palpitations and chest dyspnea, and the eldest sister of the index case died suddenly at the age of50. The age of onset of symptomatic ARVC was50.5±6.38years. Regional wall motion abnormalities were identified by2-DE in right ventricular free wall in all patients. During follow-up,2-DE revealed biventricular dilation with RV aneurysm in the proband's elder sister. Despite the systolic impairment in proband's younger brother, the NYHA functional class remained II. Twelve-lead ECG demonstrated extended T wave inversion. Except for the youngest sister, all patients presented with Epsilon wave after the QRS complex and the terminal activation delay was90.5±18.8(65-120) ms. The eldest brother had no epsilon waves upon S-ECG, when initially diagnosed ARVC. Four years later, QRS complex was widen and Epsilon waves were detected in precordial leads. In this family, all were homoozygous for the F531C mutation in DSG2, and this mutation was highly conservative in different species.
Conclusion: Mutations in DSG2display a high degree of penetrance. Dynamic changes of ECG and2-DE suggest ARVC is a progressive disease with LV involvement as a prominent feature in this family.
Part Ⅱ:Transcriptome profiling and molecular biological study reveals a major role for DSG2in the pathogenesis of ARVC
Background:Desmoglein-2(DSG2) is transmembrane cell adhesion protein of desmosomes. Mutations of DSG2have been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting that DSG2may play a role in the pathogenesis of ARVC. In our previous study, we found the loss of DSG2recapitulate the molecular changes of ARVC. However, no study has examined the mechanistic contribution of DSG2deficiency to ARVC.
Objectives:The aim of our study is to investigate the loss of DSG2on the apoptosis of HL-1cell and changes of transcriptome profiling.
Methods:A set of DSG2-specific siRNAs were synthesized and cloned into the vectors pGPU6/GFP/Neo. The recombinant plasmids pGPU6/GFP/Neo-ShDSG2(ShDSG2) were transfected into HL-1cells, and the positive cells clones were screened with G418. The suppression effect of DSG2mRNA and protein was measured by RT-PCR and Western blot to select the optimal cell line. NimbleGen mRNA microarray were used to examine differentially expressed genes between normal HL-1cells and DSG2silenced HL-1cells.
Results:Four recombinant ShDSG2plasmids were constructed successfully and transfected into HL-1cells to induce RNAi, and stable cell lines were enstablished. ShDSG2-273group could effectively knockdown the DSG2gene expression in mRNA level (71.67%, P=0.004) and in protein level (51.72%, P<0.001), as compared with the normal HL-1cell line. We found2282differential expressed gene (up-regulated820genes, down-regulated1404genes). Meanwhile, Gene Ontology analysis showed significant alteration of gene functions such as cardiac muscle fiber development, actomyosin structure organization and regulation of heart contraction. Cardiac ion channels composed of potassium and calcium were significantly decreased after DSG downregulation. In addition, KEGG Pathway analysis demonstrated deregulation of many important signaling pathways including Tyrosine metabolism, MAPK signaling pathway and Cell Communication. Moreover, we found that loss of DSG2activated AKT/beta-catenin.
Conclusion:Loss of DSG2in HL-1cell produced broad transcription changes that were similar to human ARVC. The occurrence of apoptosis, remodeling of Cx43and deregulation of ion channels may contribute to the pathogenesis of ARVC.
Part Ⅲ:The estabilishement and analysis the phenotype of cardiac-specific DSG2F536c transgenic mice
Background:In our previous study, we found a highly conservative mutation F531C in DSG2gene associated arrhythmogenic right ventricular cardiomyopathy (ARVC). However, the relationship between this mutation and ARVC is unclear.
Objective:To generate the cardiac-specific DSG2F536C expression transgenic mice and to determine the cardiac functional and morphological changes of the mice.
Methods:The transgenic vector was constructed by inserting the mouse DSG2F536C gene into the downstream of α-MHC promoter. The transgenic mice were created by the method of micro injection. The genotype of the transgenic line was identified by PCR and the expression level of the gene was determined by Western blot. The pathologic changes were analyzed with echocardiography and Masson staining.
Results:Three lines of B6CBF1DSG2F536C and two lines of DSG2WT transgenic mice were established. The high expressed line was smaller than the littermates after birth. The histological examination of Tg-H transgenic mice showed increased size of cardiomyocytes and decreased percent fractional shortening (FS%) compared with the DSG2WTtransgenic mice by echocardiography analysis. Myocardial hypertrophy and fibrosis were observed by histological analysis.
Conclusions The DSG2F536C transgenic mice produce a similar pathological phenotype with the human arrhythmogenic right ventricular cardiomyopathy (ARVC). The transgenic mice could be a useful animal model to explore the mechanisms of mutation in DSG2causing ARVC.
引文
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