Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, 117599, Singapore.
Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, 117599, Singapore; Cardiac Department, National University Health System, Tower Block Level 9, 1E Kent Ridge Road, 119228, Singapore; Christchurch Heart Institute, Department of Medicine, University of Otago, PO Box 4345, Christchurch 8014, New Zealand.
Biochim Biophys Acta Mol Basis Dis. 2017 Aug;1863(8):2031-2040. doi: 10.1016/j.bbadis.2016.12.019. Epub 2017 Jan 5.
Heart failure (HF) is a widely prevalent syndrome imposing a significant burden of morbidity and mortality world-wide. Differential circulating microRNA profiles observed in HF cohorts suggest the diagnostic utility of microRNAs as biomarkers. Given their function in fine tuning gene expression, alternations in microRNA landscape could reflecting the underlying mechanisms of disease and present potential therapeutic targets. Using multiple computational target predicting algorithms together with the luciferase-based reporting platform, the interactions between HF-related microRNAs and the 3' untranslated regions (3'UTRs) of neurohormone associated genes were examined and compared. Our results indicate that although in silico prediction provides an overview of possible microRNA-mRNA target pairs, less than half of the predicted interactions were experimentally confirmed by reporter assays in HeLa cells. Thus, the establishment of microRNA/3'UTR reporters is essential to systemically evaluate the roles of microRNAs for signaling cascades of interest, including cardiovascular neurohormonal signaling. The physiological relevance of HF-related microRNAs on the expression of putative gene targets was further established by using gain-of-function assays in two human cardiac-derived cells. Our findings, for the first time, provide direct evidence of the regulatory effects of HF-related microRNAs on the neurohormonal signaling in cardiac cells. More importantly, our study presents a rational approach to further exploring microRNA profiling data in deciphering the role of microRNA in complex syndromes such as HF. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.
心力衰竭（HF）是一种广泛流行的综合征，在全球范围内造成了重大的发病率和死亡率负担。HF 患者群体中观察到的循环微小 RNA 谱差异表明微小 RNA 作为生物标志物具有诊断效用。鉴于它们在精细调节基因表达中的功能，微小 RNA 景观的改变可能反映了疾病的潜在机制，并提供了潜在的治疗靶点。使用多种计算靶标预测算法和基于荧光素酶的报告平台，研究了与 HF 相关的微小 RNA 与神经激素相关基因的 3'非翻译区（3'UTR）之间的相互作用，并进行了比较。我们的结果表明，尽管计算机预测提供了可能的微小 RNA-mRNA 靶标对的概述，但通过 HeLa 细胞中的报告基因测定实验验证的预测相互作用不到一半。因此，建立微小 RNA/3'UTR 报告基因对于系统地评估微小 RNA 对感兴趣的信号级联（包括心血管神经激素信号）的作用至关重要。通过在两种人类心脏来源的细胞中进行功能获得性测定，进一步确立了 HF 相关微小 RNA 对假定基因靶标的表达的生理相关性。我们的研究结果首次提供了 HF 相关微小 RNA 对心脏细胞中神经激素信号的调节作用的直接证据。更重要的是，我们的研究提出了一种合理的方法，用于进一步探索微小 RNA 谱数据，以阐明微小 RNA 在心力衰竭等复杂综合征中的作用。本文是一个特刊的一部分，题为：心力衰竭的遗传和表观遗传控制-由 Jun Ren 和 Megan Yingmei Zhang 编辑。
