Systems Biology in Chronic Heart Failure—Identification of Potential miRNA Regulators

Abstract

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 (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.

Non-coding RNAs in the pathophysiology of heart failure with preserved ejection fraction

“…miR-30b plasma levels were found downregulated in HFpEF patients ( 130 , 131 ). In combination with 6 other miRNA plasma levels (let-7a-5p, miR-107, miR-125a-5p, miR139-5p, miR-150-5p and miR-342-3p), miR-30b-5p levels were able to discriminate between HFpEF and HFrEF patients, where miR-30b-5p levels were reduced in HFpEF compared to HFrEF ( 131 ), showing the potential of this miRNA as a biomarker of HFpEF.…”

“…miR-30b plasma levels were found downregulated in HFpEF patients ( 130 , 131 ). In combination with 6 other miRNA plasma levels (let-7a-5p, miR-107, miR-125a-5p, miR139-5p, miR-150-5p and miR-342-3p), miR-30b-5p levels were able to discriminate between HFpEF and HFrEF patients, where miR-30b-5p levels were reduced in HFpEF compared to HFrEF ( 131 ), showing the potential of this miRNA as a biomarker of HFpEF. Plasma levels of miR-30c were also found to be lower expressed in HF, and in combination with BNP, miR-221, miR-328, and miR-375 plasma levels, was able to differentiate between HFpEF and HFrEF patients, where miR-30c levels tend to be lower in HFrEF compared to HFpEF ( 132 ).…”

“…Plasma levels of let-7a-5p were downregulated in patients with chronic HF, and combined with the levels of 6 other miRNAs (miR-107, miR-125a-5p, miR139-5p, miR-150-5p, miR-30b-5p and miR-342-3p) can be utilized to discriminate HFpEF from HFrEF patients ( 131 ). Similarly, in a sensory neuropathy rat model for diastolic dysfunction, let-7a-5p was downregulated in the heart ( 71 ).…”

The molecular mechanisms in prenatal drug exposure-induced fetal programmed adult cardiovascular disease

“…Fetuses exposed to antibiotic mixtures induced postnatal downregulation of let-7a-5p ( Xuan et al, 2022 ). Let-7a-5p had been identified as a biomarker in failing hearts that regulated the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), which mediated autophagy ( Vilella-Figuerola et al, 2022 ). The inhibition of let-7a-5p increased the level of IGF2BP3 and led to more apoptosis and autophagy of cardiomyocytes in anoxia/reoxygenation (A/R) injuries ( Gan et al, 2020 ).…”

miRNA Dysregulation in Cardiovascular Diseases: Current Opinion and Future Perspectives

“…Over the past 15 years, a large number of experimental studies have contributed to clarifying the functions of several miRNAs involved in regulatory processes at the cardiac level [ 4 , 5 ]. Various studies have highlighted the pivotal role of certain miRNAs in hypertrophy, heart failure, and myocardial infarction, considering that they may be involved both in degenerative and reparative processes in cardiomyocytes [ 6 , 7 , 8 , 9 , 10 , 11 ]. Furthermore, given the intrinsic nature of the heart which is a muscle, several experimental studies focused on the involvement of the so-called myo-miRNAs as mediators and markers of cardiac damage [ 12 , 13 ].…”