Circulating Non-Coding RNAs as Indicators of Fibrosis and Heart Failure Severity

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, representing a complex clinical syndrome in which the heart's ability to pump blood efficiently is impaired. HF can be subclassified into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), each with distinct pathophysiological mechanisms and varying levels of severity. The progression of HF is significantly driven by cardiac fibrosis, a pathological process in which the extracellular matrix undergoes abnormal and uncontrolled remodelling. Cardiac fibrosis is characterized by excessive matrix protein deposition and the activation of myofibroblasts, increasing the stiffness of the heart, thus disrupting its normal structure and function and promoting lethal arrythmia. MicroRNAs, long non-coding RNAs, and circular RNAs, collectively known as non-coding RNAs (ncRNAs), have recently gained significant attention due to a growing body of evidence suggesting their involvement in cardiac remodelling such as fibrosis. ncRNAs can be found in the peripheral blood, indicating their potential as biomarkers for assessing HF severity. In this review, we critically examine recent advancements and findings related to the use of ncRNAs as biomarkers of HF and discuss their implication in fibrosis development.

Keywords: HFpEF; HFrEF; biomarkers; cardiac fibrosis; circular RNAs; heart failure; long non-coding RNAs; microRNAs; ncRNAs.

Figure 2

ncRNAs as HF circulating biomarkers. The diagram highlights how circulating ncRNAs act as biomarkers and regulators in HF by modulating hypertrophy (light pink bottom section), fibrosis (blue section), and cardiomyocyte death (dark pink section). Circulating ncRNAs are classified into anti-fibrotic (green ovals), pro-fibrotic (red ovals), and ones with unknown effects in fibrosis (blue ovals), while their specific targets are shown in beige boxes. Arrows and inhibition symbols represent their regulatory actions: activation (→): promotes the downstream target; inhibition (⊥): suppresses the downstream target; dashed lines (---): indicate interactions based on data from non-cardiac tissues or cells. Briefly, circFNDC3B, circCDR1as, miR-150-5p (via inhibiting EGR1), and miR-29b-5p (by inhibiting TGF-β and MMP2) suppress cardiac fibrosis [57,67,192,203,204], while CASC7 (by sponging miR-30c and upregulating IL-11), NRON (by promoting NFATc3 phosphorylation), miR-497-5p, miR-107 (by targeting BDNF), miR-21-5p, and PVT1 (by sponging miR-128-3p and miR-145 and upregulating HCN1 and TGF-β) promote cardiac fibrosis [39,52,83,104,141,144,145,219]. CircBPTF, LIPCAR, miR-182-5p, and miR-423-5p are shown as circulating in HF, with their role in fibrosis validated in other cells/tissues than just cardiac ones (vascular, lung) [73,80,124,187]. Similarly, miR-423-5p (via the Wnt/β-catenin pathway), NRF (by sponging miR-873 and upregulating RIPK1/3), and circC12ORF51 promote cardiomyocyte death [138,205,215], while HOTAIR (by sponging miR-17 and upregulating RORA) diminished it [116]. miR-21-5p and NRON, as well as iR-27a-3p and miR-423-5p, facilitate cardiac hypertrophy by downregulating their respective targets NOVA1 and SUPT6H [56,142,215,228]. Meanwhile, HOTAIR targets PTEN to regulate cardiac hypertrophy [222]. Acronyms: BDNF, brain-derived neurotrophic factor; BPTF, Bromodomain PHD Finger Transcription Factor; CASC7, Cancer Susceptibility Candidate 7; EGR1, Early Growth Response Protein 1; FNDC3B, Fibronectin Type III Domain Containing 3B; HCN1, Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1; HOTAIR, HOX Transcript Antisense RNA; IL11, Interleukin 11; LIPCAR, Long Intergenic Non-Protein Coding RNA, Cardiac-Associated; MMP2, Matrix Metalloproteinase-2; NFATc3, Nuclear factor of activated T-cells, cytoplasmic 3; NOVA1, Neuro-oncological ventral antigen 1; NRON, non-coding repressor of NFAT; PTEN, Phosphatase and Tensin homologue; RIPK1/RIPK3, Receptor-Interacting Protein Kinase 1/3; ROCK1/ROCK2, Rho-associated protein kinase 1/2; RORA, Retinoic Acid Receptor-Related Orphan Receptor Alpha; SUPT6H, Suppressor of Ty 6 homologue; TGF-β1, Transforming growth factor beta 1; TUSC7, Tumor Suppressor Candidate 7; URI1, Unconventional Prefoldin RPB5 Interactor 1; and Wnt, Wingless and Int-1. Created in BioRender, https://BioRender.com/v93w259 (accessed on 27 December 2024).

Figure 4

Circulating ncRNAs associated with cardiac remodelling. The figure depicts the involvement of circulating ncRNAs across three HF-related conditions (coronary disease, myocardial infarction, and hypertrophic cardiomyopathy) in regulating fibrosis (blue section), cardiomyocyte death (dark pink section), and hypertrophy (light pink). Circulating ncRNAs are classified into anti-fibrotic (green ovals), pro-fibrotic (red ovals), and ones with unknown effects in fibrosis (blue ovals), while their specific targets are shown in beige boxes. Arrows and inhibition symbols represent their regulatory actions: activation (→): promotes the downstream target; inhibition (⊥): suppresses the downstream target; and dashed lines (---): indicate interactions based on data from non-cardiac tissues or cells. Briefly, among ncRNAs circulating in myocardial infarction, MIAT (via PI3K/Akt), MALAT (by activating YAP and TGF-β), and UCA1 (in liver) are pro-fibrotic [110,127,135,159,160,250], while circLAS1L and circZNF609 are anti-fibrotic (the latter is demonstrated in lung fibrosis) [166,185,206]. CHAST and MFACR have not yet been reported as playing a role in fibrosis, though CHAST promotes hypertrophy and represses cardiomyocyte death by downregulating Plekhm1. UCA1 facilities hypertrophy via miR-184/HOXA9 and MFACR acts as a positive hypertrophy regulator via miR-652-3p/MTP18 [106,107,159,161,208,209]. MALAT1 also increases apoptosis via miR-144-3p [128]. Among the ncRNAs circulating in coronary disease, H19 and circHIPK3 are pro-fibrotic by upregulating TGF-β [112,198,244,254], whereas circROBO2 promotes cardiomyocyte death [210]. The roles of circDNAJ6, circTMEM56, and circMBOAT2 in the heart, shown circulating in hypertrophic cardiomyopathy, remain to be further elucidated [207]. Acronyms: ADCY6, Adenylyl cyclase type 6; Akt, Protein kinase B; BACE1-AS, Beta-Secretase-1 Antisense RNA; CHAST, Cardiac Hypertrophy-Associated Transcript; DNAJC6, DnaJ heat shock protein family (Hsp40) member C6; DUSP5, Dual specificity protein phosphatase 5; ERK1/2, Extracellular signal-regulated kinases; HIPK3, Homeodomain-Interacting Protein Kinase 3; LAS1L, LAS1-Like Ribosome Biogenesis Factor; MBOAT2, Membrane-Bound O-Acyltransferase Domain Containing 2; MTP18, Mitochondrial protein 18 kDa; HOXA9, Homeobox protein Hox-A9; MALAT1, Metastasis-associated lung adenocarcinoma transcript 1; MFACR, Mitochondrial fission and apoptosis-related circRNA; MIAT, MI-associated transcript; PI3K, Phosphoinositide 3-kinases; Plekhm1, Pleckstrin homology domain-containing family M member 1; TGF-β, Transforming growth factor β; ROBO2, Roundabout Guidance Receptor 2; SMARCA5, SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin Subfamily A Member 5; TMEM56, Transmembrane Protein 56; TRADD, Tumor necrosis factor receptor type 1-associated DEATH domain protein; UCA1, urothelial carcinoma-associated 1; YAP, Yes-associated protein; and ZNF609, Zinc Finger Protein 609. Created in BioRender, https://BioRender.com/r50y649 (accessed on 28 December 2024).

Figure 1

Structure of the heart under healthy and pathological conditions, with differing levels of circulating ncRNAs in the bloodstream. In the healthy heart, the myocardium is predominantly populated with cardiomyocytes. The bloodstream contains various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). In HFpEF, the LV wall is thickened, and the myocardium undergoes reactive fibrosis. Circulating ncRNAs (miRNAs, lncRNAs, circRNAs) are altered in expression (indicated by different colours), indicating their role in the fibrotic and HF processes. In HFrEF, the LV wall is thinned and accompanied by replacement fibrosis, with loss of cardiomyocytes. The expression profiles of circulating ncRNAs are altered in HF, indicating their potential as biomarkers for disease subtypes [7,8,10]. Acronyms: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction. Created in BioRender, https://BioRender.com/e51z267 (accessed on 27 December 2024).

Figure 3

ncRNAs associated with HFpEF and HFrEF. The schematic highlights circulating molecular biomarkers associated with Heart Failure with preserved Ejection Fraction (HFpEF) and Heart Failure with reduced Ejection Fraction (HFrEF). Change in expression of ncRNAs are indicated with arrows (↑ for upregulation; ↓ for downregulation). For HFpEF, biomarkers such as miR-18b-5p and miR-19b-3p [38,50] are decreased, while lncRNAs (e.g., MHRT, CARMEN, TUG1, FENDRR) and circRNA circHECW2 are elevated [101,161,216]. Conversely, in HFrEF, miRNAs like miR-375, miR-328, and miR-125a-5p [43,46,74] are modulated, alongside increased lncRNAs (e.g., SRA1, HEAT2) and circRNA circDEPCS [92,149,171]. Acronyms: CARMEN, Cardiac Mesoderm Enhancer-associated Non-coding; DEPC5, DEP Domain Containing 5, GATOR1 Subcomplex Subunit; FENDRR, FOXF1 Adjacent Non-coding Developmental Regulatory RNA; HEAT2, heart-disease-associated transcript 2; HECW2, HECT, C2 And WW Domain Containing E3 Ubiquitin Protein Ligase 2; MHRT, myosin heavy-chain-associated RNA; SRA1, steroid receptor RNA activator 1; and TUG1, taurine upregulated 1. Created in BioRender, https://BioRender.com/f60l673 (accessed on 27 December 2024).