The diagnostic value of circulating microRNAs in heart failure

Abstract

Heart failure (HF) is a complex clinical syndrome, characterized by inadequate blood perfusion of tissues and organs caused by decreased heart ejection capacity resulting from structural or functional cardiac disorders. HF is the most severe heart condition and it severely compromises human health; thus, its early diagnosis and effective management are crucial. However, given the lack of satisfactory sensitivity and specificity of the currently available biomarkers, the majority of patients with HF are not diagnosed early and do not receive timely treatment. A number of studies have demonstrated that peripheral blood circulating nucleic acids [such as microRNAs (miRs), mRNA and DNA] are important for the diagnosis and monitoring of treatment response in HF. miRs have been attracting increasing attention as promising biomarkers, given their presence in body fluids and relative structural stability under diverse conditions of sampling. The aim of the present review was to analyze the associations between the mechanisms underlying the development of HF and the expression of miRs, and discuss the value of using circulating miRs as diagnostic biomarkers in HF management. In particular, miR-155, miR-22 and miR-133 appear to be promising for the diagnosis, prognosis and management of HF patients.

Keywords: circulating microRNAs; diagnostic biomarkers; heart failure.

Figure 1.

Association between miRs and different pathogenic mechanisms of heart failure. Solid lines represent positive regulation and dashed lines represent negative regulation. The nock of the arrow controls the tip of the arrow, for example miR-7a/b downregulates Sp1, PARP-1 and caspase-3, whereas Sp1, PARP-1 and caspase-3 promote myocardial fibrosis. Therefore, miR-7a/b protects cardiomyocytes against apoptosis. CFL2, Cofilin-2; HMGB1, high-mobility group box 1 protein; HSBP1, Heat Shock Factor Binding Protein 1; ACE2, Angiotensin-convertingenzyme2; Bcl-2, B-cell lymphoma-2; SRF, serum response factor; TAGLN2, Transgelin 2; NFATC4, Nuclear Factor Of Activated T Cells; CTGF, connective tissue growth factor; DOX, Doxorubicin; MMP-9, matrix metalloproteinase-9; β1AR and β2AR, β1-and β2-adrenoceptor; TGF-β, transforming growth factor-β; IL-1β, Interleukin-1β; MCP1, monocyte chemoattractant protein-1; PDCD4, programmed cell death 4; SP1, specific protein 1; PARP1, poly ADP-ribose polymerase; ALDO, aldosterone; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; Akt, Protein Kinase B; Col1a1, collagen 1A1; Col1a2, collagen 1A2; col15a1, collagen 15A1; Col III, type III collagen; Col I, type I collagen; MAPK, mitogen-activated protein kinase; VEGF, Vascular endothelial growth Factor; ERK, extracellular regulated protein kinases; MMP-2, matrix metalloproteinase-2; SPRY1, Protein sprouty homolog 1.

Figure 2.

Association between miRs and different pathogenic mechanisms of heart failure. Solid lines represent positive regulation and dashed lines represent negative regulation. The nock of the arrow controls the tip of the arrow, for example miR-451 downregulates the LKB1/AMPK pathway, and the LKB1/AMPK pathway negatively regulates the tendency for cardiomyocyte hypertrophy. Therefore, miR-451 promotes myocardial hypertrophy. JUN, Jun proto-oncogene product which is a subunit of the AP-1 transcription; HOXA9, Homeobox A9; UCA1, urothelial carcinoma-associated 1; KLF13, Kruppel-like transcription factor 13; CIAPIN1, cytokine-induced anti-apoptotic molecule; BDNF, brain derived neurotrophic factor; TGFβ-1, transforming growth factor β-1; Bcl-2, B-cell lymphoma-2; APAF-1, apoptotic protease activating factor-1; SGK, Serum and Glucocorticoid Induced Kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; ITGB3, integrin β3; PTEN, phosphatase and tensin homolog deleted on chromosome 10; MCU, mitochondrial calcium uptake; INSR, insulin receptor; IGFR1, Insulin-like growth factor 1 receptor; SIRT4, Sirtuin-4; fos-AP1, Fos-Associated Protein 1; MMP, matrix metalloproteinase; AMPK, adenosine monophosphate-activated protein kinase; LKB1, Liver kinase B1; NF-κB, nuclear factor kappaB; TRAF3, TNF receptor associated factor 3; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; AP-1, activator protein-1; ALK-5, activin-like kinase 5; PKC, protein kinase C; CAV3, Caveolin 3; ROS, reactive oxygen species; COX, cycloxygenase.

Figure 3.

MiRNAs in different heart failure have different regulatory mechanisms for pathogenesis of heart failure. Solid lines represent positive regulation and dashed lines represent negative regulation. The nock of the arrow controls the tip of the arrow, for example, upregulation of miR-22 in diabetic heart failure alleviated myocardial inflammation through inhibiting tumor necrosis factor-α or interleukin-6 expression. TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; AP-1, activator protein-1; HMGB1, high-mobility group box 1 protein; Bcl-2, B-cell lymphoma-2; TAGLN2, Transgelin 2; NFATC4, Nuclear Factor Of Activated T Cells; LKB1, Liver kinase B1; AMPK, adenosine monophosphate-activated protein kinase; MMP-9, matrix metalloproteinase-9; CAV3, Caveolin 3; PKC, protein kinase C; PDCD4, programmed cell death 4; ALDO, aldosterone; CIAPIN1, cytokine-induced anti-apoptotic molecule; KLF13, Kruppel-like transcription factor 13; SGK, Serum and Glucocorticoid Induced Kinase; SP1, specific protein 1; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; MMP-2, matrix metalloproteinase-2; Col1a1, collagen 1A1; Col III, type III collagen; Col I, type I collagen; PARP 1, poly ADP-ribose polymerase 1.