Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 23, Pages -Publisher
MDPI
DOI: 10.3390/ijms232315226
Keywords
miRNA; chronic heart failure; network; enrichment pathways; pathophysiology
Funding
- Research Grant of the Spanish Society of Cardiology (SEC-2016)
- Spanish Ministry of Economy and Competitiveness of Science Agencia Estatal de Investigacion (AEI)
- Institute of Health Carlos III (ISCIII) [AEI/10.13039/501100011033-[PID2019-107160RB-I00]]
- H2020-JTI-IMI2-2017-13-two-stage Project [Red RICORS TERAV-RD21/0017/0013, FIS PI19/01687]
- Cardiovascular Program-ICCC (IR-HSCSP) [TRANSBIOLINE 821283]
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This study analyzed the miRNA patterns in patients with chronic heart failure (HF) and identified pathways involved in the pathophysiology of HF. Several miRNAs were found to be up-regulated in HF patients and their combinations could discriminate between different types of HF. The study also proposed novel cellular mechanisms involved in the pathogenesis of chronic HF.
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-beta signaling. By ROC curve analysis, combined probabilities of these seven miRNAs (let-7a-5p, miR-107, miR-125a-5p, miR-139-5p, miR-150-5p, miR-30b-5p and miR-342-3p; 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 miR-107, miR-139-5p and miR-150-5p, involved in clusters 5 and 7 (C:5+7), discriminated HFpEF from HFrEF. Pathway enrichment analysis of miRNAs present in C:1-4 (let-7a-5p, miR-125a-5p, miR-30b-5p and miR-342-3p) 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.
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