MR-1在血管紧张素Ⅱ诱导心肌肥厚中的作用研究
摘要
MR-1(Myofibrillogenesis regulatorl,肌纤基因调节因子)编码基因是从人体骨骼肌cDNA文库中获得的与心肌肥厚相关的一个新基因,位于人类第2条染色体(NT_005403.11)上,跨越2887bp片段,由3个外显子组成。在细胞水平的研究发现,MR-1与血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)诱导的心肌细胞肥大有关,并且在过表达MR-1的小鼠中发现MR-1是通过活化NF-κB恶化AngⅡ诱导的心肌肥厚。在此基础上,本研究拟在动物体内通过降低MR—1的表达研究其与AngⅡ致心肌肥厚的关系,以探讨其作为防治心肌肥厚新靶点的可能性。为此,我们首先构建了腺病毒重组载体AdSiR-MR-1,然后采用雄性C57BL/6小鼠和背部置入ALZET微型注射泵,经背部皮下灌注AngⅡ(溶于PBS),同时,设立对照PBS泵入组和对照未置入组。两周后,经超声心动图检查、小鼠心脏形态学、组织学、RT—PCR和Western分析,确定成功建立了AngⅡ诱导的小鼠心肌肥大的模型。
进而利用所构建的模型通过颈静脉和尾静脉分别注射腺病毒重组载体AdSiR-MR-1,研究了不同途径和不同剂量沉默MR1基因表达的效果。最后确定以2×10~9pfu/100μl/只的病毒量术后第二天经颈静脉注射1次,13天后进行小鼠心脏的超声心动图检查、免疫组织学检查,同时对心肌肥厚标志基因如心钠素(ANF)、β-肌球蛋白(β-myosin)、胶原纤维蛋白(collagenⅢ)进行RT—PCR和/或Western检测,结果表明在此条件下AdSiR-MR-1能够明显的抑制AngⅡ所致的心肌肥厚,同时降低肥厚标志基因如ANF、β-myosin、collagenⅢ的表达,降低心肌的纤维化。Southern-blot分析证明注射13天后腺病毒载体DNA可以在小鼠心肌组织中检出。
采用基因芯片技术检测表明在AngⅡ诱导小鼠心肌沉默MR-1基因表达后,可引起2倍上调的基因1453个,超过10倍上调的有6个;下调超过2倍的基因1081个,而超过10倍下调的有43个。基因表达变化的基因主要涉及参与肌肉收缩、免疫反应、Ca离子、G蛋白信号和代谢等多种通路途径。比较MR-1沉默组与AngⅡ处理组可发现多种肌肉收缩蛋白差异表达(有21个)、与基质蛋白相关差异表达有51个、与代谢相关的有117个、细胞信号传导蛋白表达差异的有219个,其中与G-蛋白相关表达差异的有135个、MAPK通路相关的有42个,和钙离子相关的差异表达有175个,其中97个与钙离子的结合相关、25个与钙信号通路相关,12个与钙通道相关。比较值得注意的是MR-1沉默组中有9个HSP蛋白和8个硫氧还蛋白表达上调。以上分析为我们探讨MR-1在AngⅡ诱导的心肌肥厚中的作用机制提供了思路。
通过对基因芯片分析提示的几个有显著差异表达基因的RT—PCR和/或Western检测,表明在AngⅡ诱导心肌肥厚小鼠中沉默MR1基因的表达,其心肌中热休克蛋白72、硫氧还蛋白的表达明显提高,而钙调神经磷酸酶CaAβ表达降低。这一结果提示MR1在AngⅡ诱导小鼠心肌肥厚作用中包含了对热休克蛋白、硫氧还蛋白和钙调神经磷酸酶的调节机制。本研究为探讨MR-1在AngⅡ诱导的心肌肥厚中的作用机制提供了思路,并展示了MR—1作为防治AngⅡ诱导心肌肥厚新靶点的可能性。
Myofibrillogenesis regulator-1 (MR-1) was cloned from a human skeletal muscle cDNA library. The MR-1 gene (NCBI GeneBank accession no. AF417001) is located on human chromosome 2q35 (AC021016) and spans about 2887 bp of contiguous DNA. The MR-1 gene is composed of three distinct exons and encodes a protein of 142 amino acids. Myofibrillogenesis regulator-1 (MR-1) as a novel homo gene augments cardiomyocytes hypertrophy induced by AngII in vivo and in vitro. Overexpression of MR1 aggravates cardiac hypertrophy induced by AngII in mice. In this study the effect of silencing MR-1 with RNAi on cardiac hypertrophy induced by AngII in mice was investigated. Cardiac hypertrophy mice was induced by chronic infusion of AngII through implanted pumps. Recombinant adenoviral vector (pAdxsi) expressing MR-1 SiRNA was constructed and used to treat cardiac hypertrophy in mice. AdSiR-MR-1 was administered to the mice via the jugular or tail vein at first in order to define the route of delivery and the effective silencing dose. Significant silencing was observed with 2×10~9 pfu of AdSiR-MR-1 via jugular vein. Western blot analysis showed that AdSiR-MR-1 effectively silenced the expression of MR-1 in cardiomyocytes as well as in other tissues except the skeletal muscle. AdSiR-MR-1 suppressed dose-dependent myocardial MR-1 protein expression in AngII-infused mice. Administration of AdSiR-MR-1 via the jugular vein almost abolished the overexpression of MR-1 induced by AngII resulting in decreased left-ventricular hypertrophy assessed by echocardiography. Moreover, cardiac hypertrophy-related protein levels, such as ANF, andβ-myosin were attenuated significantly in the heart of AngII-infused mice by knockdown of MR-1. AdSiR-MR-1 treatment also significantly diminishes the cardiac fibrosis accompanied with the decrease of collagen contents as observed morphologically and by immunohistochemical determination. Our results identify, for the first time, that MR-1 serves as a new target in protecting and suppressing cardiac hypertrophy induced by AngII in vivo.
Genechip microarray expression analysis ( Affymetrix, over 18, 000cDNA sequences) was applied to evaluate the changes in the genes expression in AngII-infused AdSiR-MR-1 treated mice verse to AngII-infused mice without treatment(control). About 1453 genes expression were increased in more than two fold, among them 6 genes were expressed in ten fold higher than control. In the same time 1081 genes were expressed lower in two fold more and 43 genes expression were decreased in ten fold comparing with control. The altered expression genes mostly involved in the pathways related to muscle relaxation and contraction, immune reaction, G-protein related signaling , calcium ion binding or regulation as well as amino-acid metabolisms. Differentially expressed genes in AdSiR-MR-1 treated mice could be grouped into the functions of muscle contraction and relaxation, signaling transduction, calcium ion biding and signaling etc. Nine genes encoding for heat shock proteins (HSP) and eight genes encoding for thioredoxins (TRX) were up-regulated and eighty four genes related to calcium functions were down-regulated in AdSiR-MR-1 treated mice vs control.. The up-regulated gene expression of HSP72 and TRX as well as down-regulated calcineurin gene expression were confirmed by RT-PCR and Western blot analyses. These findings indicate the possible involvement of HSPs, TRXs and calcineurin in the MR1 regulatory pathways governing the development of cardiac hypertrophy induced by AngII. This work paves the way for better understanding of MR1 regulation mechanism in cardiac hypertrophy induced by AngII and suggests that MR1 would be considered as a new target for the treatment or prevention of cardiac hypertrophy and heart failure in future.
进而利用所构建的模型通过颈静脉和尾静脉分别注射腺病毒重组载体AdSiR-MR-1,研究了不同途径和不同剂量沉默MR1基因表达的效果。最后确定以2×10~9pfu/100μl/只的病毒量术后第二天经颈静脉注射1次,13天后进行小鼠心脏的超声心动图检查、免疫组织学检查,同时对心肌肥厚标志基因如心钠素(ANF)、β-肌球蛋白(β-myosin)、胶原纤维蛋白(collagenⅢ)进行RT—PCR和/或Western检测,结果表明在此条件下AdSiR-MR-1能够明显的抑制AngⅡ所致的心肌肥厚,同时降低肥厚标志基因如ANF、β-myosin、collagenⅢ的表达,降低心肌的纤维化。Southern-blot分析证明注射13天后腺病毒载体DNA可以在小鼠心肌组织中检出。
采用基因芯片技术检测表明在AngⅡ诱导小鼠心肌沉默MR-1基因表达后,可引起2倍上调的基因1453个,超过10倍上调的有6个;下调超过2倍的基因1081个,而超过10倍下调的有43个。基因表达变化的基因主要涉及参与肌肉收缩、免疫反应、Ca离子、G蛋白信号和代谢等多种通路途径。比较MR-1沉默组与AngⅡ处理组可发现多种肌肉收缩蛋白差异表达(有21个)、与基质蛋白相关差异表达有51个、与代谢相关的有117个、细胞信号传导蛋白表达差异的有219个,其中与G-蛋白相关表达差异的有135个、MAPK通路相关的有42个,和钙离子相关的差异表达有175个,其中97个与钙离子的结合相关、25个与钙信号通路相关,12个与钙通道相关。比较值得注意的是MR-1沉默组中有9个HSP蛋白和8个硫氧还蛋白表达上调。以上分析为我们探讨MR-1在AngⅡ诱导的心肌肥厚中的作用机制提供了思路。
通过对基因芯片分析提示的几个有显著差异表达基因的RT—PCR和/或Western检测,表明在AngⅡ诱导心肌肥厚小鼠中沉默MR1基因的表达,其心肌中热休克蛋白72、硫氧还蛋白的表达明显提高,而钙调神经磷酸酶CaAβ表达降低。这一结果提示MR1在AngⅡ诱导小鼠心肌肥厚作用中包含了对热休克蛋白、硫氧还蛋白和钙调神经磷酸酶的调节机制。本研究为探讨MR-1在AngⅡ诱导的心肌肥厚中的作用机制提供了思路,并展示了MR—1作为防治AngⅡ诱导心肌肥厚新靶点的可能性。
Myofibrillogenesis regulator-1 (MR-1) was cloned from a human skeletal muscle cDNA library. The MR-1 gene (NCBI GeneBank accession no. AF417001) is located on human chromosome 2q35 (AC021016) and spans about 2887 bp of contiguous DNA. The MR-1 gene is composed of three distinct exons and encodes a protein of 142 amino acids. Myofibrillogenesis regulator-1 (MR-1) as a novel homo gene augments cardiomyocytes hypertrophy induced by AngII in vivo and in vitro. Overexpression of MR1 aggravates cardiac hypertrophy induced by AngII in mice. In this study the effect of silencing MR-1 with RNAi on cardiac hypertrophy induced by AngII in mice was investigated. Cardiac hypertrophy mice was induced by chronic infusion of AngII through implanted pumps. Recombinant adenoviral vector (pAdxsi) expressing MR-1 SiRNA was constructed and used to treat cardiac hypertrophy in mice. AdSiR-MR-1 was administered to the mice via the jugular or tail vein at first in order to define the route of delivery and the effective silencing dose. Significant silencing was observed with 2×10~9 pfu of AdSiR-MR-1 via jugular vein. Western blot analysis showed that AdSiR-MR-1 effectively silenced the expression of MR-1 in cardiomyocytes as well as in other tissues except the skeletal muscle. AdSiR-MR-1 suppressed dose-dependent myocardial MR-1 protein expression in AngII-infused mice. Administration of AdSiR-MR-1 via the jugular vein almost abolished the overexpression of MR-1 induced by AngII resulting in decreased left-ventricular hypertrophy assessed by echocardiography. Moreover, cardiac hypertrophy-related protein levels, such as ANF, andβ-myosin were attenuated significantly in the heart of AngII-infused mice by knockdown of MR-1. AdSiR-MR-1 treatment also significantly diminishes the cardiac fibrosis accompanied with the decrease of collagen contents as observed morphologically and by immunohistochemical determination. Our results identify, for the first time, that MR-1 serves as a new target in protecting and suppressing cardiac hypertrophy induced by AngII in vivo.
Genechip microarray expression analysis ( Affymetrix, over 18, 000cDNA sequences) was applied to evaluate the changes in the genes expression in AngII-infused AdSiR-MR-1 treated mice verse to AngII-infused mice without treatment(control). About 1453 genes expression were increased in more than two fold, among them 6 genes were expressed in ten fold higher than control. In the same time 1081 genes were expressed lower in two fold more and 43 genes expression were decreased in ten fold comparing with control. The altered expression genes mostly involved in the pathways related to muscle relaxation and contraction, immune reaction, G-protein related signaling , calcium ion binding or regulation as well as amino-acid metabolisms. Differentially expressed genes in AdSiR-MR-1 treated mice could be grouped into the functions of muscle contraction and relaxation, signaling transduction, calcium ion biding and signaling etc. Nine genes encoding for heat shock proteins (HSP) and eight genes encoding for thioredoxins (TRX) were up-regulated and eighty four genes related to calcium functions were down-regulated in AdSiR-MR-1 treated mice vs control.. The up-regulated gene expression of HSP72 and TRX as well as down-regulated calcineurin gene expression were confirmed by RT-PCR and Western blot analyses. These findings indicate the possible involvement of HSPs, TRXs and calcineurin in the MR1 regulatory pathways governing the development of cardiac hypertrophy induced by AngII. This work paves the way for better understanding of MR1 regulation mechanism in cardiac hypertrophy induced by AngII and suggests that MR1 would be considered as a new target for the treatment or prevention of cardiac hypertrophy and heart failure in future.
引文
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