Vilella-Figuerola Alba, Gallinat Alex, Escate Rafael, Mirabet Sònia, Padró Teresa, Badimon Lina
Cardiovascular-Program-ICCC, IR-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain.
Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain.
Int J Mol Sci. 2022 Dec 3;23(23):15226. doi: 10.3390/ijms232315226.
Heart failure (HF) is a complex disease entity with high clinical impact, poorly understood pathophysiology and scantly known miRNA-mediated epigenetic regulation. We have analysed miRNA patterns in patients with chronic HF (cHF) and a sex- and age-matched reference group and pursued an in silico system biology analysis to discern pathways involved in cHF pathophysiology. Twenty-eight miRNAs were identified in cHF that were up-regulated in the reference group, and eight of them were validated by RT-qPCR. In silico analysis of predicted targets by STRING protein-protein interaction networks revealed eight cluster networks (involving seven of the identified miRNAs) enriched in pathways related to cell cycle, Ras, chemokine, PI3K-AKT and TGF-β signaling. By ROC curve analysis, combined probabilities of these seven miRNAs (, , , , , and ; clusters 1-4 [C:1-4]), discriminated between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), and ischaemic and non-ischaemic aetiology. A combination of , and , involved in clusters 5 and 7 (C:5+7), discriminated HFpEF from HFrEF. Pathway enrichment analysis of miRNAs present in C:1-4 (, , and ) revealed pathways related to HF pathogenesis. In conclusion, we have identified a differential signature of down-regulated miRNAs in the plasma of HF patients and propose novel cellular mechanisms involved in cHF pathogenesis.
心力衰竭（HF）是一种具有高临床影响的复杂疾病实体，其病理生理学知之甚少，且miRNA介导的表观遗传调控也鲜为人知。我们分析了慢性心力衰竭（cHF）患者以及性别和年龄匹配的参照组中的miRNA模式，并进行了计算机系统生物学分析，以识别参与cHF病理生理学的通路。在cHF中鉴定出28种miRNA在参照组中上调，其中8种通过RT-qPCR得到验证。通过STRING蛋白质-蛋白质相互作用网络对预测靶点进行的计算机分析揭示了8个聚类网络（涉及7种已鉴定的miRNA），这些网络在与细胞周期、Ras、趋化因子、PI3K-AKT和TGF-β信号传导相关的通路中富集。通过ROC曲线分析，这7种miRNA（，，，，，和；聚类1-4 [C:1-4]）的联合概率可区分射血分数保留的心力衰竭（HFpEF）和射血分数降低的心力衰竭（HFrEF），以及缺血性和非缺血性病因。参与聚类5和7（C:5+7）的、和的组合可区分HFpEF和HFrEF。对C:1-4中存在的miRNA（，，和）进行的通路富集分析揭示了与HF发病机制相关的通路。总之，我们在HF患者血浆中鉴定出下调的miRNA的差异特征，并提出了参与cHF发病机制的新细胞机制。
