MicroRNAs-The Heart of Post-Myocardial Infarction Remodeling

Abstract

Myocardial infarction (MI) is one of the most frequent cardiac emergencies, with significant potential for mortality. One of the major challenges of the post-MI healing response is that replacement fibrosis could lead to left ventricular remodeling (LVR) and heart failure (HF). This process involves canonical and non-canonical transforming growth factor-beta (TGF-β) signaling pathways translating into an intricate activation of cardiac fibroblasts and disproportionate collagen synthesis. Accumulating evidence has indicated that microRNAs (miRNAs) significantly contribute to the modulation of these signaling pathways. This review summarizes the recent updates regarding the molecular mechanisms underlying the role of the over 30 miRNAs involved in post-MI LVR. In addition, we compare the contradictory roles of several multifunctional miRNAs and highlight their potential use in pressure overload and ischemia-induced fibrosis. Finally, we discuss their attractive role as prognostic biomarkers for HF, highlighting the most relevant human trials involving these miRNAs.

Keywords: biomarker; heart failure; left ventricular remodeling; miRNA; myocardial infarction; prognostic.

Figure 1

Schematic representation of the canonical TGF-β signaling pathway and related miRNAs.

Figure 2

Schematic representation of the non-canonical TGF-β signaling pathway and related miRNAs. MiRNAs colored in green have an anti-fibrotic function; miRNAs colored in red have a pro-fibrotic role. Dash-line arrows indicate the translocation of proteins from the cytoplasm to the nucleus or vice versa; solid line arrows indicate signaling cascades; yellow stars indicate transcription factors. α-SMA, alfa smooth muscle actin, AKT, protein kinase B; c-fos, Fos Proto-Oncogene, AP-1 transcription factor subunit, COL1A1, collagen type 1, alpha 1 gene; COL1A2, collagen type 1, alpha 2 gene; CTGF, connective tissue growth factor; EGR-1, early growth response protein 1; ELN, elastin gene; ERK, extracellular signal-regulated kinase, FBN, fibrillin gene; IRAK1, interleukin-1 receptor-associated kinase 1; JAG1, jagged 1 protein; JNK, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOTCH1, Notch receptor 1; P38, p38 mitogen-activated protein kinases; PI3K, phosphoinositide 3-kinases; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog protein; Raf, Proto-Oncogene, Serine/Threonine Kinase; Ras, Ras Proto-Oncogene, GTPase family; RI, transforming growth factor beta receptor I; RII, transforming growth factor beta receptor II; S6K, ribosomal protein S6 kinase beta-1; Smad 2, 3, 4, 2/3, SMAD family members; TAK1, mitogen-activated protein kinase kinase kinase 7 or transforming growth factor-beta-activated kinase 1; TGF-β, transforming growth factor beta, TRAF6, tumor necrosis factor receptor associated factor 6.