MicroRNA-421 Dysregulation is Associated with Tetralogy of Fallot.
MicroRNA-421 Dysregulation is Associated with Tetralogy of Fallot.
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DOI：
10.3390/cells3030713
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发表时间：
2014-07-11
期刊：
影响因子：
6
通讯作者：
O'Brien JE
中科院分区：
文献类型：
--
作者：
Bittel DC;Kibiryeva N;Marshall JA;O'Brien JE
microRNA对于维持发育中的脊椎动物心脏稳定性的重要性最近变得显而易见。此外，人们越来越认识到microRNA在发育病理学中的重要性，包括先天性心脏缺陷的形成。我们检查了特发性法洛四联症（TOF，无22 q11.2缺失）婴儿右心室（RV）心肌中微小RNA的表达，发现与正常发育的对照受试者相比，TOF儿童心肌中61种微小RNA的表达发生了显着变化（奥布莱恩等人，2012年）。具有改变表达的microRNA的预测靶点富集了调节心脏发育的基因网络。我们先前推导出了已知对心脏发育至关重要的229个基因的列表，并发现44个基因在TOF心肌中的表达相对于正常发育的心肌有显著变化。这44个基因与33个microRNA呈显著负相关，每个microRNA的表达也发生了显著变化。在这里，我们专注于miR-421，因为它在TOF婴儿的RV组织中显著上调;预计与心血管调节途径的多个成员相互作用;并已被证明可调节细胞增殖。我们分别在TOF婴儿和正常发育心脏婴儿的RV来源的原代细胞中敲低和过表达miR-421。我们发现miR-421和SOX 4的表达之间存在显著的负相关性，SOX 4是Notch通路的关键调节因子，已被证明对心脏流出道很重要。这些发现表明，miR-421的失调作为法洛四联症的潜在贡献者值得进一步研究。
The importance of microRNAs for maintaining stability in the developing vertebrate heart has recently become apparent. In addition, there is a growing appreciation for the significance of microRNAs in developmental pathology, including the formation of congenital heart defects. We examined the expression of microRNAs in right ventricular (RV) myocardium from infants with idiopathic tetralogy of Fallot (TOF, without a 22q11.2 deletion), and found 61 microRNAs to be significantly changed in expression in myocardium from children with TOF compared to normally developing comparison subjects (O’Brien et al. 2012). Predicted targets of microRNAs with altered expression were enriched for gene networks that regulate cardiac development. We previously derived a list of 229 genes known to be critical to heart development, and found 44 had significantly changed expression in TOF myocardium relative to normally developing myocardium. These 44 genes had significant negative correlations with 33 microRNAs, each of which also had significantly changed expression. Here, we focus on miR-421, as it is significantly upregulated in RV tissue from infants with TOF; is predicted to interact with multiple members of cardiovascular regulatory pathways; and has been shown to regulate cell proliferation. We knocked down, and over expressed miR-421 in primary cells derived from the RV of infants with TOF, and infants with normally developing hearts, respectively. We found a significant inverse correlation between the expression of miR-421 and SOX4, a key regulator of the Notch pathway, which has been shown to be important for the cardiac outflow track. These findings suggest that the dysregulation of miR-421 warrants further investigation as a potential contributor to tetralogy of Fallot.