沉默MR-1对血管紧张素Ⅱ诱导小鼠心肌肥厚基因表达谱的影响

Gene Expression Profiling Study of Angiotensin Ⅱ-induced Cardiac Hypertrophy in Response to Silencing MR-1

肌纤基因调节因子(myofibrillogenesis regulator1,MR1)是首次从人体骨骼肌cDNA文库中分离得到的基因.以前的研究证明MR1能够介导血管紧张素Ⅱ(AngⅡ)诱导的体内外心肌肥厚效应,但相关分子机制有待进一步阐明.利用腺病毒载体在小鼠中沉默MR1表达,利用基因芯片对比检查了小鼠心肌基因表达谱的变化.结果发现,在AngⅡ诱导心肌肥厚的小鼠,沉默MR1前后出现明显的信号通路方面的变化和基因表达差异,其中沉默MR1后表达降低90%以上的基因有39个,而表达升高10倍以上的基因有5个.在这些基因中,对与心肌肥厚密切相关的基因进行了定量RT-PCR检测,以进一步验证基因芯片的结果,发现沉默MR1后HSP72和硫氧还蛋白1(Trx1)均表达升高,而钙调神经磷酸酶β(CnAβ)和β肌球蛋白(β-myosin)的基因表达则受抑制.这些信号通路和基因均与AngⅡ诱导的心肌肥厚有一定的关系,为揭示MR1在AngⅡ所致心肌肥厚中的作用和分子机制提供了新的证据.

Myofibrillogenesis regulatorl （MR1） was first identified from a human skeletal muscle cDNA library in the laboratory, and the previous studies have proved the role of MR1 in Angiotensin II （Ang Ⅱ ） -induced cardiac hypertrophy both in vivo and in vitro. However, relevant underlying molecular mechanisms of MR1 in Ang lI induced cardiac hypertrophy remain to be elucidated. Gene silencing of MR1 by adenovirus-delivered siRNA approach in mice was used, and microarray analysis of myocardial gene expressions was compared before and after MR1 silencing along with Ang Ⅱ treatment. Significant changes of genes expression in several pathways, such as pathways involved in cardiac hypertrophy and mTOR signaling etc., were observed between the two groups. Furthermore, genes that were changed by 10 folds after MR1 silencing were totally listed, with 39 genes being down-regulated and 5 up-regulated. To further verify the microarray results, some of genes that are suggested to be closely related to cardiac hypertrophy were detected by quantitative RT-PCR. As a result, HSP72 and thioredoxin 1 （Trxl） expression were increased, while the calcineurin Phosphatase β （CnAβ） and β-myosin （β-myosin） expression were suppressed upon MR1 silencing. These signaling pathways and genes are closely correlated with cardiac hypertrophy induced by Ang Ⅱ. The alterations of relevant pathways and genes may help understand the molecular role of MR1 in Ang Ⅱ -induced cardiac hypertrophy.