MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling

Abstract

MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length. Increasing evidence implicates miRs in myocardial disease processes. Here we show that miR-199b is a direct calcineurin/NFAT target gene that increases in expression in mouse and human heart failure, and targets the nuclear NFAT kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (Dyrk1a), constituting a pathogenic feed forward mechanism that affects calcineurin-responsive gene expression. Mutant mice overexpressing miR-199b, or haploinsufficient for Dyrk1a, are sensitized to calcineurin/NFAT signalling or pressure overload and show stress-induced cardiomegaly through reduced Dyrk1a expression. In vivo inhibition of miR-199b by a specific antagomir normalized Dyrk1a expression, reduced nuclear NFAT activity and caused marked inhibition and even reversal of hypertrophy and fibrosis in mouse models of heart failure. Our results reveal that microRNAs affect cardiac cellular signalling and gene expression, and implicate miR-199b as a therapeutic target in heart failure.

Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

“…These previous findings support our finding that miR‐133a is closely related to cardiac hypertrophy. The specificity of the relation between miR‐133a, CTGF, and asymmetric hypertrophy in LBBB hearts is further emphasized by the lack of local overexpression of miR‐199b and miR‐155f, which are often up‐regulated during pressure overload and concentric hypertrophy 13, 14. These results from a clinically relevant large animal model support the concept that miR‐133a plays an important role in the hypertrophic response of cardiomyocytes under conditions of increased myocardial strain.…”

“…miR‐1, miR‐133a, miR‐155f, and miR‐199b have been linked to cardiac hypertrophy,11, 12, 13, 14 while miR‐29c and miR‐30c were described in cardiac fibrosis 15, 16, 17. Furthermore, miR‐146a, miR‐146b, miR‐222, and miR‐499 were included in the analysis 18.…”

Plasma MicroRNAs Relate to Atrial Fibrillation Recurrence after Catheter Ablation: Longitudinal Findings from the MiRhythm Study

“…Plasma miRNAs 199B, 30A, and 601 are related to AF recurrence , another plasma miRNA related to AF recurrence in our study, has previously been implicated in the pathogenesis of heart disease, especially heart failure [30]. MiRNA 199b targets Dyrk1a, which in turn is an activator of the NFAT/calcineurin-signaling pathway.30 Up-regulation of this pathway induces pathologic expression of "fetal" cardiac genes, such as β-myosin heavy chain, which is known to be up regulated in both murine and human models of heart failure [30].…”

“…MiRNA 199b targets Dyrk1a, which in turn is an activator of the NFAT/calcineurin-signaling pathway.30 Up-regulation of this pathway induces pathologic expression of "fetal" cardiac genes, such as β-myosin heavy chain, which is known to be up regulated in both murine and human models of heart failure [30]. MiRNA 199b also targets several ubiquitin ligases involved in proteasome activity, such that an increase in the ubiquitinproteasome system as mediated by miRNA 199b leads to pathologic structural remodeling and ventricular dilatation [31].…”

Exercício físico e microRNAs: novas fronteiras na insuficiência cardíaca

“…In the hearts of individuals with HF without LVAD, a significant increase in the expression of 28 miRNAs was observed, while in those treated with LVAD, 20 of these miRNAs were completely normalized, and the other eight tended to normalization. Experimental studies 32 have shown that a phenotype can be reversed through the inhibition of a specific miRNA that has an increased expression in this condition. This can be accomplished by administering an anti-miRNA oligonucleotide, which acts as a competitive inhibitor of that miRNA and is called antagomiR.…”