2013年3月13日讯 /生物谷BIOON/ --来自伊利诺伊大学的Madhu Gupta教授带领他的团队在《生物化学杂志》（Journal of biological chemistry）上在线发表了题为"A cardiac enriched microRNA, miR-378 blocks cardiac hypertrophy by targeting Ras-signaling"的文章。文章中指出，他们发现在心肌细胞中富集表达的microRNA-378通过靶向Ras信号通路，参与抑制心肌肥厚的发生。
心肌肥厚指心肌细胞增大而无细胞分裂，是心肌细胞对高血压、瓣膜病、急性心肌梗塞及先天性心脏病等疾病的一种基本应答，长期应激所致的持续性心肌肥厚最终可导致扩张性心肌病、心衰和猝死。已有研究表明，Ras信号通路在心肌肥厚过程中发挥了重要作用，Ras通路通过激活下游IGF-PI3K-AKT-mTOR和Raf1-MEK1-ERK1/2两条通路，引起心肌肥厚的发生。
MicroRNA（miRNA）是一类内源产生的，长约22nt的单链非编码小RNA，参与转录后基因表达调控。众多miRNA被证明在心脏发育和心脏疾病发生过程中发挥着重要功能，仅在心肌细胞中特异性表达的miR-378就是其中之一。本文就miR-378在刺激剂导致的心肌肥厚过程中发挥的作用进行了系统性的研究。
在此项研究中，研究者们探索了miR-378的表达和心肌肥厚的相互关系，他们发现，在刺激剂导致的心肌肥厚过程中miR-378的表达被抑制，这一结果在细胞水平和动物水平都得到了验证，同时，过表达miR-378可以有效的阻滞此类心肌肥厚的发生。这一结果证实，miR-378确实参与了刺激剂导致的心肌肥厚的发生过程，起着负调节的作用。
在进一步的研究中，研究人员对miR-378所参与的信号通路进行了探索。他们对刺激剂引起的心肌肥厚过程中几条重要的信号通路进行研究，发现miRNA-378通过对Ras通路进行负调节从而抑制了MAPK/ERK和PI3K/AKT两条通路的激活。通过使用生物信息学预测，研究者们对这条通路上可能存在的miR-378靶点进行了分析和实验验证，结果表明，miR-378靶向Ras通路上游的Grb-2，通过抑制该蛋白的表达从而对Ras通路进行负调控。
此项研究指出了miR-378在心肌肥厚过程中起到的重要作用，为心肌肥厚引起的心脏疾病的治疗研究提供的新的思路。（生物谷Bioon.com）
doi:10.1074/jbc.M112.442384
A cardiac enriched microRNA, miR-378 blocks cardiac hypertrophy by targeting Ras-signaling
Raghu S. Nagalingam1, Nagalingam R. Sundaresan2, Mahesh P. Gupta2,Dave Geenen1, R. John Solaro1 and Madhu Gupta1,*
Understanding the regulation of cardiomyocyte growth is crucial for the management of adverse ventricular remodeling and heart failure. MicroRNA-378 (miR-378) is a newly described member of the cardiac enriched miRNAs which is expressed only in cardiac myocytes and not in cardiac fibroblasts. We have previously shown that miR-378 regulates cardiac growth during post-natal period by direct targeting of IGF1R (J Biol Chem 287, 12913-12926, 2012). Here, we report that miR-378 is an endogenous negative regulator of cardiac hypertrophy, and its levels are down regulated during hypertrophic growth of the heart and during heart failure. In primary cultures of cardiomyocytes, over expression of miR-378 blocked PE-stimulated Ras-activity and it also prevented activation of two major growth-promoting signaling pathways, PI3K-AKT and Raf1-MEK1-ERK1/2, acting downstream of Ras-signaling. Over expression of miR-378 suppressed PE-induced phosphorylation of S6 ribosomal kinase, pERK1/2, pAKT, pGSK3β and nuclear accumulation of NFAT. There was also suppression of fetal gene program that was induced by PE. Experiments carried out to delineate the mechanism behind the suppression of Ras, led us to identify Grb2, an upstream component of Ras-signaling, as a bone-fide direct target of miR-378-mediated regulation. Deficiency of miR-378 alone was sufficient to induce fetal gene expression, which was prevented by knocking down of Grb2 expression and by blocking of Ras-activation, thus suggesting that miR-378 interferes with Ras-activation by targeting Grb2. Our study demonstrates that miR-378 is an endogenous negative regulator of Ras-signaling and cardiac hypertrophy and its deficiency contributes to the development of cardiac hypertrophy.
