Hepc1对扩张型心肌病的调节机制研究
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摘要
背景Hepcl是主要在肝脏表达的一种小分子抗菌肽,是铁代谢的负调节激素。Hepc1在心脏中少量表达,是一种内在的心脏调节激素,它的表达同样受到低氧和炎症的调节,并与心脏局部铁代谢相关,而且铁是一种重要的参与心脏心脏功能调节的离子。
cTnTR92Q转基因小鼠心脏变大,室壁变厚,心腔变小,心肌细胞排列紊乱,间质纤维化,心肌舒张功能失调,而cTnTR141w转基因小鼠的全心扩大,室壁变薄,间质纤维化,心肌收缩功能失调,分别表现出典型的肥厚型和扩张型心肌病病理表型。两种疾病模型动物心脏全基因表达芯片及逆转录PCR结果显示,Hepc1在两种转基因动物模型的心脏中的表达均下调。
扩张型心肌病是一种以心腔(左心室和/或右心室)扩张、心肌收缩功能受损为主要特征的原因不明的心肌疾病,是除冠心病和高血压以外导致心力衰竭的主要病因之一,5年内病死率高达15-50%。本研究的目的是建立心脏组织特异的Hepc1转基因小鼠,探究该基因在扩张型心肌病发生发展中的作用。
方法cTnTa141w与cTnTR92Q全基因表达芯片及逆转录PCR检测Hepc1于扩张型心肌病及肥厚型心肌病模型小鼠中的表达变化。RT-PCR法克隆Hepc1基因,将基因插入a-MHC启动子下游,构建转基因表达载体,通过显微注射法建立Hepc1转基因C57/6J小鼠。PCR法鉴定Hepc1转基因小鼠的基因型,RT-PCR检测基因转录水平,狭缝杂交检测蛋白表达水平,确定高表达首建鼠。Hepc1转基因小鼠与cTnTR141W转基因小鼠杂交建立Hepcl×cTnTR141w杂交小鼠。M型超声心动图检测不同月龄Hepc1、 cTnTR141W及Hepcl×cTnTR141w转基因小鼠心脏的结构形态和功能变化。HE染色和Masson染色观察Hepc1、cTnTR141w及Hepc1×cTnTR141w转基因小鼠心脏组织学改变。透射电镜分析心肌超微结构改变。Western blot检测心脏肥大标记物ATP2A2的表达水平变化；RT-PCR检测Col1al及Acta1的表达。Western blot险测Hepc1、cTnTR141w及Hepcl×cTnTR141w转基因小鼠心脏中p-ERK及ERK表达水平。将Hepc1基因插入CMV启动子下游构建CMV-Hepc1表达载体,脂质体转染法转染H9c2细胞建立过表达CMV-Hepc1稳转细胞系。分别用DFO及FAC对H9c2细胞进行铁剥夺和对CMV-Hepc1稳转细胞系铁增强试验,Western blot检测各细胞系中p-ERK及ERK表达水平变化。
结果cTnTR141w与cTnTR92Q全基因表达芯片及逆转录PCR显示,Hepc1在两种转基因小鼠心脏中均表达下降。建立了2个心脏特异表达的Hepc1转基因小鼠品系。Hepc1基因在心脏组织的表达水平超过内源性Hepc1的3倍。同时建立了心脏特异表达的Hepc1×cTnTR141w杂交小鼠。M型超声心动图及心脏组织学显示,心脏特异表达的Hepc1转基因小鼠的心室室壁增厚,心腔变小,心功能增强；组织学结果显示,心肌细胞排列发生轻度重塑,其余结构未见异常；电镜超微结构可见,心肌纤维增粗,偶见巨大线粒体。与cTnTR141W转基因小鼠相比,Hepc1×cTnTR141w杂交小鼠心室室壁增厚,心腔变小,心收缩功能明显改善。超微结构可见,Hepc1×cTnTR141w杂交小鼠心肌肌纤维增粗,肌纤维断裂溶解现象得到明显改善。反映心脏功能的钙调节相关蛋白基因ATP2A2在cTnTR141W转基因小鼠心脏中表达下调,而在Hepc1×cTnTR141w杂交小鼠心脏中表达增加。反映心肌间质胶原成分的Colla1及细胞骨架相关蛋白Acta1在皆在Hepc1×cTnTR141w杂交小鼠心脏中表达下调,Hepc1显著逆转了cTnTR141W转基因小鼠心脏中的表达增加。4月龄cTnTR141W转基因小鼠出现早期死亡,至6月龄早期死亡率达16%,Hepc1转基因小鼠未出现早期死亡,而且Hepc1×cTnTR14W转基因小鼠与cTnTR141w转基因小鼠相比,死亡率相对较低。cTnTR141w转基因小鼠心脏中p-ERK水平相对于野生成年小鼠显著下降,而在Hepc1×cTnTR141w杂交小鼠心脏ERK磷酸化水平升高。体外实验表明,铁剥夺时ERK磷酸化水平升高,同时铁剥夺和铁增强时ERK磷酸化水平恢复。
结论建立了2个心脏特异表达的Hepc1转基因小鼠品系。Hepc1转基因可明显改善cTnTR141W扩张型心肌病病理表型。Hepc1下调心脏组织中的铁浓度,并诱导ERK激活。这些结果说明Hepc1是通过铁的调节改善扩张性心肌病的病理发展。Hepc1有可能成为治疗心肌病的靶基因之一。
背景两种疾病模型动物心脏基因表达芯片结果显示,Lrp2bp在扩张型心肌病动物模型心肌中mRNA显著上调表达,而在肥厚型心肌症动物模型心肌中表达较少,Lrp2bp可能参与心肌病发生发展。建立了心脏特异表达的低密度脂蛋白受体相关蛋白2结合蛋白(Lrp2bp)转基因小鼠,研究该基因在心肌病发病中的作用。
方法Western blot检测小鼠Lrp2bp表达谱。克隆鼠源Lrp2bp基因入a-MHC启动子下游构建a-MHC-Lrp2bp表达载体,显微注射法建立Lrp2bp转基因小鼠。PCR鉴定转基因首建鼠的基因型。Western blotting鉴定Lrp2bp在心脏中的表达,心脏超声检测转基因鼠及野生型小鼠心脏功能及几何构型,透射电镜观察心肌细胞的超微结构改变。
结果Lrp2bp主要在成年小鼠肾脏组织中表达,肝、脾中表达较高,心、肺和脑组织中表达量少,在心脏中的表达不随年龄而改变。得到了4个Lrp2bp转基因品系,其中3个品系心脏Lrp2bp蛋白表达量与同龄野生型鼠相比明显增加。1M龄转基因小鼠与同窝阴性对照小鼠相比,心壁变厚,心腔变大,射血分数和短轴缩短率下降。
结论成功建立了心脏特异表达的1rp2bp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。
Objective Hepcidin is a hormone mainly expressed in the tissues of liver, which is invovled in the signals of Fe2+in cell. Hepcidin expresses in heart tissue and it is possible to regulate the function of Fe2+, which has been indicated invovled the physiological function of heart and pathogenesis of heart disese. The paper reported the establishment of heart specific Hepcl transgenic mice and analysis of the effect of the gene Hepcl on the deveopment of dilated cardiomyopathy in the cTnTR141w transgenic mice.
Methods The expression of Hepcl gene in both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) mice were analyzed using gene expression microarray of cTnTR92Q and cTnTR141w myocardium and confirmed by reverse transcriptional polymerase chain reaction (RT-PCR). The transgenic vector was constructed by inserting the mouse Hepc1gene into the downstream of a-MHC promoter. The transgenic mice were created by the method of microinjection. The genotype of transgenic mice of cTnTR141W, Hepc1and Hepc1xcTnTR141w was detected by PCR, the expression level of the Hepc1gene was determined by RT-PCR and slot blotting. Pathologic changes were observed by light microscopy and transmission electronic microscopy. The cardiac structure and function were analyzed with M-mode echocardiography. Survival data of the experimental mice were recorded. The cardiac hypertrophic marker genes were analyzed by RT-PCR and western blotting. The accumulation of p-ERKl/2and ERK1/2were determined by western blotting in wild type, cTnTR141w, Hepcl xcTnTR141w and Hepcl transgenic mice. The expression construct for Hepcl was generated by cloning a PCR-amplified full-length cDNA fragment into pcDNA3.1+vector. H9c2cell line was transfected with Hepc1construct using Lipofectamine2000. The expression level of p-ERK1/2and ERK1/2were also detected in H9c2, DFO-treated H9c2, CMV-Hepcl and FAC-treated CMV-Hepcl cell lines.
Results Gene expression microarray analysis, RT-PCR and slot blotting revealed that a lower expression of Hepc1in both DCM mice and HCM mice. C57BL/6J transgenic mice carrying the Hepc1, HepclxcTnTR141w and cTnTR141w genes were all established. The heart of Hepc1transgenic mice showed hypertrophic ventricular wall, reduced ventricular chamber, diastolic dysfunction compared with that of wild type. Thicker myofiber and more mitochondrias of the Hepcl transgenic mice were observed under the transmission electronic microscope. All the pathological changes of Hepcl transgenic mice display light left ventricular hypertrophy. The Hepcl×cTnTR141w transgenic mice showed a thicker ventricular wall, smaller ventricular chamber, improved diastolic function, elongated and lysed myofrils when compared with cTnTR141w transgenic mice. The genes of extracellular matrix protein Col1al, the genes of cytoskeletal protein Actal, were significantly decreased in Hepc1and Hepcl xcTnTR141w transgenic mice, which were increased in cTnTR141w transgenic mice. The gene of calcium-regulation protein ATP2A2was shown to be increased in Hepc1and Hepc1×cTnTR141w transgenic mice,which were decreased in cTnTR141w transgenic mice. Immature death occurred after4months of age and the immature death rate was16%before6months of age in the cTnTR141w mice, while HepclxcTnTR141w transgenic mice showed a low immature death compared with that of cTnTR141w transgenic mice, but higher than that of WT mice. An accumulation of p-ERKl/2was seen both DFO-treated H9c2and CMV-Hepcl cell lines compared with H9c2cell line and FAC-treated CMV-Hepc1cell line. ERK1/2phosphorylation was increased in Hepcl and Hepcl×cTnTR141w transgenic mice compared with cTnTR141w transgenic mice.
Conclusions Two heart specific Hepcl transgenic mice lines were established. The Hepcl transgenic mice exihibited an marked improvement on the pathologic phenotype of the cTnTR141w transgenic mice. Hepcl downregulated the iron level in heart tissue, and induced the activation of ERK1/2. These data indicates Hepc1delays the pathophysiological process by downregulation of iron in the heart tissue and it may be a new target in the treatment of dilated cardiomyopathy.
Objectives To generate the heart-specific Lrp2bp overexpressing mice, a model for the study of its function and effects on cardiomyopathy.
Methods The transgenic vector was constructed by inserting the murine Lrp2bp gene into the downstream of a-MHC promoter. The transgenic mice were created by the method of microinjection. The genotype of transgenic line was identified by PCR and the expression level of the gene was determined by Western blotting. The cardiac function and geometry were detected by echocaridiography. The uLtrastructure changes of cardiomyocytes from Lrp2bp tg mice were observed by transmission electron microsopy.
ResuLts Three lines of C57BL/6J transgenic mice with high level of Lrp2bp expression were identified from four transgenic founders. The heart of1-month-old Lrp2bp transgenic mice showed signficantly increased ventricuLar wall, dilated ventricuLar chamber compared with that of wild type whereas ejection fraction (EF%) and fractionl shortening (FS%) were markedly decreased.
Conclusions The transgenic mice with cardiac-specific expression of the murine Lrp2bp gene were establised successfuLly and it can be used to crossbreed with the DCM and the HCM models to investigate the function of Lrp2bp gene on the development of caridomyopathy.
cTnTR92Q转基因小鼠心脏变大,室壁变厚,心腔变小,心肌细胞排列紊乱,间质纤维化,心肌舒张功能失调,而cTnTR141w转基因小鼠的全心扩大,室壁变薄,间质纤维化,心肌收缩功能失调,分别表现出典型的肥厚型和扩张型心肌病病理表型。两种疾病模型动物心脏全基因表达芯片及逆转录PCR结果显示,Hepc1在两种转基因动物模型的心脏中的表达均下调。
扩张型心肌病是一种以心腔(左心室和/或右心室)扩张、心肌收缩功能受损为主要特征的原因不明的心肌疾病,是除冠心病和高血压以外导致心力衰竭的主要病因之一,5年内病死率高达15-50%。本研究的目的是建立心脏组织特异的Hepc1转基因小鼠,探究该基因在扩张型心肌病发生发展中的作用。
方法cTnTa141w与cTnTR92Q全基因表达芯片及逆转录PCR检测Hepc1于扩张型心肌病及肥厚型心肌病模型小鼠中的表达变化。RT-PCR法克隆Hepc1基因,将基因插入a-MHC启动子下游,构建转基因表达载体,通过显微注射法建立Hepc1转基因C57/6J小鼠。PCR法鉴定Hepc1转基因小鼠的基因型,RT-PCR检测基因转录水平,狭缝杂交检测蛋白表达水平,确定高表达首建鼠。Hepc1转基因小鼠与cTnTR141W转基因小鼠杂交建立Hepcl×cTnTR141w杂交小鼠。M型超声心动图检测不同月龄Hepc1、 cTnTR141W及Hepcl×cTnTR141w转基因小鼠心脏的结构形态和功能变化。HE染色和Masson染色观察Hepc1、cTnTR141w及Hepc1×cTnTR141w转基因小鼠心脏组织学改变。透射电镜分析心肌超微结构改变。Western blot检测心脏肥大标记物ATP2A2的表达水平变化；RT-PCR检测Col1al及Acta1的表达。Western blot险测Hepc1、cTnTR141w及Hepcl×cTnTR141w转基因小鼠心脏中p-ERK及ERK表达水平。将Hepc1基因插入CMV启动子下游构建CMV-Hepc1表达载体,脂质体转染法转染H9c2细胞建立过表达CMV-Hepc1稳转细胞系。分别用DFO及FAC对H9c2细胞进行铁剥夺和对CMV-Hepc1稳转细胞系铁增强试验,Western blot检测各细胞系中p-ERK及ERK表达水平变化。
结果cTnTR141w与cTnTR92Q全基因表达芯片及逆转录PCR显示,Hepc1在两种转基因小鼠心脏中均表达下降。建立了2个心脏特异表达的Hepc1转基因小鼠品系。Hepc1基因在心脏组织的表达水平超过内源性Hepc1的3倍。同时建立了心脏特异表达的Hepc1×cTnTR141w杂交小鼠。M型超声心动图及心脏组织学显示,心脏特异表达的Hepc1转基因小鼠的心室室壁增厚,心腔变小,心功能增强；组织学结果显示,心肌细胞排列发生轻度重塑,其余结构未见异常；电镜超微结构可见,心肌纤维增粗,偶见巨大线粒体。与cTnTR141W转基因小鼠相比,Hepc1×cTnTR141w杂交小鼠心室室壁增厚,心腔变小,心收缩功能明显改善。超微结构可见,Hepc1×cTnTR141w杂交小鼠心肌肌纤维增粗,肌纤维断裂溶解现象得到明显改善。反映心脏功能的钙调节相关蛋白基因ATP2A2在cTnTR141W转基因小鼠心脏中表达下调,而在Hepc1×cTnTR141w杂交小鼠心脏中表达增加。反映心肌间质胶原成分的Colla1及细胞骨架相关蛋白Acta1在皆在Hepc1×cTnTR141w杂交小鼠心脏中表达下调,Hepc1显著逆转了cTnTR141W转基因小鼠心脏中的表达增加。4月龄cTnTR141W转基因小鼠出现早期死亡,至6月龄早期死亡率达16%,Hepc1转基因小鼠未出现早期死亡,而且Hepc1×cTnTR14W转基因小鼠与cTnTR141w转基因小鼠相比,死亡率相对较低。cTnTR141w转基因小鼠心脏中p-ERK水平相对于野生成年小鼠显著下降,而在Hepc1×cTnTR141w杂交小鼠心脏ERK磷酸化水平升高。体外实验表明,铁剥夺时ERK磷酸化水平升高,同时铁剥夺和铁增强时ERK磷酸化水平恢复。
结论建立了2个心脏特异表达的Hepc1转基因小鼠品系。Hepc1转基因可明显改善cTnTR141W扩张型心肌病病理表型。Hepc1下调心脏组织中的铁浓度,并诱导ERK激活。这些结果说明Hepc1是通过铁的调节改善扩张性心肌病的病理发展。Hepc1有可能成为治疗心肌病的靶基因之一。
背景两种疾病模型动物心脏基因表达芯片结果显示,Lrp2bp在扩张型心肌病动物模型心肌中mRNA显著上调表达,而在肥厚型心肌症动物模型心肌中表达较少,Lrp2bp可能参与心肌病发生发展。建立了心脏特异表达的低密度脂蛋白受体相关蛋白2结合蛋白(Lrp2bp)转基因小鼠,研究该基因在心肌病发病中的作用。
方法Western blot检测小鼠Lrp2bp表达谱。克隆鼠源Lrp2bp基因入a-MHC启动子下游构建a-MHC-Lrp2bp表达载体,显微注射法建立Lrp2bp转基因小鼠。PCR鉴定转基因首建鼠的基因型。Western blotting鉴定Lrp2bp在心脏中的表达,心脏超声检测转基因鼠及野生型小鼠心脏功能及几何构型,透射电镜观察心肌细胞的超微结构改变。
结果Lrp2bp主要在成年小鼠肾脏组织中表达,肝、脾中表达较高,心、肺和脑组织中表达量少,在心脏中的表达不随年龄而改变。得到了4个Lrp2bp转基因品系,其中3个品系心脏Lrp2bp蛋白表达量与同龄野生型鼠相比明显增加。1M龄转基因小鼠与同窝阴性对照小鼠相比,心壁变厚,心腔变大,射血分数和短轴缩短率下降。
结论成功建立了心脏特异表达的1rp2bp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。
Objective Hepcidin is a hormone mainly expressed in the tissues of liver, which is invovled in the signals of Fe2+in cell. Hepcidin expresses in heart tissue and it is possible to regulate the function of Fe2+, which has been indicated invovled the physiological function of heart and pathogenesis of heart disese. The paper reported the establishment of heart specific Hepcl transgenic mice and analysis of the effect of the gene Hepcl on the deveopment of dilated cardiomyopathy in the cTnTR141w transgenic mice.
Methods The expression of Hepcl gene in both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) mice were analyzed using gene expression microarray of cTnTR92Q and cTnTR141w myocardium and confirmed by reverse transcriptional polymerase chain reaction (RT-PCR). The transgenic vector was constructed by inserting the mouse Hepc1gene into the downstream of a-MHC promoter. The transgenic mice were created by the method of microinjection. The genotype of transgenic mice of cTnTR141W, Hepc1and Hepc1xcTnTR141w was detected by PCR, the expression level of the Hepc1gene was determined by RT-PCR and slot blotting. Pathologic changes were observed by light microscopy and transmission electronic microscopy. The cardiac structure and function were analyzed with M-mode echocardiography. Survival data of the experimental mice were recorded. The cardiac hypertrophic marker genes were analyzed by RT-PCR and western blotting. The accumulation of p-ERKl/2and ERK1/2were determined by western blotting in wild type, cTnTR141w, Hepcl xcTnTR141w and Hepcl transgenic mice. The expression construct for Hepcl was generated by cloning a PCR-amplified full-length cDNA fragment into pcDNA3.1+vector. H9c2cell line was transfected with Hepc1construct using Lipofectamine2000. The expression level of p-ERK1/2and ERK1/2were also detected in H9c2, DFO-treated H9c2, CMV-Hepcl and FAC-treated CMV-Hepcl cell lines.
Results Gene expression microarray analysis, RT-PCR and slot blotting revealed that a lower expression of Hepc1in both DCM mice and HCM mice. C57BL/6J transgenic mice carrying the Hepc1, HepclxcTnTR141w and cTnTR141w genes were all established. The heart of Hepc1transgenic mice showed hypertrophic ventricular wall, reduced ventricular chamber, diastolic dysfunction compared with that of wild type. Thicker myofiber and more mitochondrias of the Hepcl transgenic mice were observed under the transmission electronic microscope. All the pathological changes of Hepcl transgenic mice display light left ventricular hypertrophy. The Hepcl×cTnTR141w transgenic mice showed a thicker ventricular wall, smaller ventricular chamber, improved diastolic function, elongated and lysed myofrils when compared with cTnTR141w transgenic mice. The genes of extracellular matrix protein Col1al, the genes of cytoskeletal protein Actal, were significantly decreased in Hepc1and Hepcl xcTnTR141w transgenic mice, which were increased in cTnTR141w transgenic mice. The gene of calcium-regulation protein ATP2A2was shown to be increased in Hepc1and Hepc1×cTnTR141w transgenic mice,which were decreased in cTnTR141w transgenic mice. Immature death occurred after4months of age and the immature death rate was16%before6months of age in the cTnTR141w mice, while HepclxcTnTR141w transgenic mice showed a low immature death compared with that of cTnTR141w transgenic mice, but higher than that of WT mice. An accumulation of p-ERKl/2was seen both DFO-treated H9c2and CMV-Hepcl cell lines compared with H9c2cell line and FAC-treated CMV-Hepc1cell line. ERK1/2phosphorylation was increased in Hepcl and Hepcl×cTnTR141w transgenic mice compared with cTnTR141w transgenic mice.
Conclusions Two heart specific Hepcl transgenic mice lines were established. The Hepcl transgenic mice exihibited an marked improvement on the pathologic phenotype of the cTnTR141w transgenic mice. Hepcl downregulated the iron level in heart tissue, and induced the activation of ERK1/2. These data indicates Hepc1delays the pathophysiological process by downregulation of iron in the heart tissue and it may be a new target in the treatment of dilated cardiomyopathy.
Objectives To generate the heart-specific Lrp2bp overexpressing mice, a model for the study of its function and effects on cardiomyopathy.
Methods The transgenic vector was constructed by inserting the murine Lrp2bp gene into the downstream of a-MHC promoter. The transgenic mice were created by the method of microinjection. The genotype of transgenic line was identified by PCR and the expression level of the gene was determined by Western blotting. The cardiac function and geometry were detected by echocaridiography. The uLtrastructure changes of cardiomyocytes from Lrp2bp tg mice were observed by transmission electron microsopy.
ResuLts Three lines of C57BL/6J transgenic mice with high level of Lrp2bp expression were identified from four transgenic founders. The heart of1-month-old Lrp2bp transgenic mice showed signficantly increased ventricuLar wall, dilated ventricuLar chamber compared with that of wild type whereas ejection fraction (EF%) and fractionl shortening (FS%) were markedly decreased.
Conclusions The transgenic mice with cardiac-specific expression of the murine Lrp2bp gene were establised successfuLly and it can be used to crossbreed with the DCM and the HCM models to investigate the function of Lrp2bp gene on the development of caridomyopathy.
引文
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