499169aa4ec9581456a3befb325f21f8 pmc_9740605.pdf cf19a80ab6e2d1dc00fd240f1f8af833685f98cf pmc_9740605.pdf 1e60749fb14f1f8f98b8edb3674e124c66612fd71d61a4b55b181cee2d73ac7b pmc_9740605.pdf Title: Systems Biology in Chronic Heart Failure—Identification of Potential miRNA Regulators Subject: 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- 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. Keywords: miRNA; chronic heart failure; network; enrichment pathways; pathophysiology Author: Alba Vilella-Figuerola, Alex Gallinat, Rafael Escate, Sònia Mirabet, Teresa Padró and Lina Badimon Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Dec 7 04:50:04 2022 CET ModDate: Wed Dec 7 05:01:00 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 22 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4908189 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WWNKGN+VnURWPalladioL Type 1 Custom yes yes no 10 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 15 0 PSACHV+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 PXZMUO+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 JOBTGI+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 GYNYLK+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 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2023-12-12 02:34:10 CET RepresentationInformation: pmc_9740605.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-08-03 02:25:01 CEST Size: 4908189 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 623 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Differential miRNA Signature in cHF Destination: subsection.2.1 Item: Title: In Silico System Biology Analysis and Target Prediction Destination: subsection.2.2 Item: Title: Association of Clusters with cHF Subtypes Destination: subsection.2.3 Item: Title: miR-107 and miR-139 Were Overrepresented in All Clusters Destination: subsection.2.4 Item: Title: Association of Individual Plasma miRNAs with Aetiology and with Left Ventricular Ejection Fraction in cHF Patients Destination: subsection.2.5 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Study Design Destination: subsection.4.1 Item: Title: Blood Sampling Destination: subsection.4.2 Item: Title: miRNA Extraction, cDNA Synthesis and Analysis Destination: subsection.4.3 Item: Title: In Silico Systems Biology Analysis Destination: subsection.4.4 Item: Title: Statistical Analysis Destination: subsection.4.5 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Systems Biology in Chronic Heart Failure Identification of Potential miRNA Regulators Author: Alba Vilella-Figuerola, Alex Gallinat, Rafael Escate, Sònia Mirabet, Teresa Padró and Lina Badimon Subject: 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- 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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