Abstract
MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length1,2. Increasing evidence implicates miRs in myocardial disease processes3,4,5,6,7,8,9,10,11. 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bartel, D. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
Pasquinelli, A. E., Hunter, S. & Bracht, J. MicroRNAs: a developing story. Curr. Opin. Genet. Dev. 15, 200–205 (2005).
Bonauer, A. et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324, 1710–1713 (2009).
van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).
Yang, B. et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nature Med. 13, 486–491 (2007).
Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).
Care, A. et al. MicroRNA-133 controls cardiac hypertrophy. Nature Med. 13, 613–618 (2007).
Liu, N. et al. microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 22, 3242–3254 (2008).
Matkovich, S. J. et al. MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ. Res. 106, 166–175.
da Costa Martins, P. A. et al. Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation 118, 1567–1576 (2008).
Thum, T. et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116, 258–267 (2007).
Olson, E. N. & Schneider, M. D. Sizing up the heart: development redux in disease. Genes Dev. 17, 1937–1956 (2003).
Hoshijima, M. & Chien, K. R. Mixed signals in heart failure: cancer rules. J. Clin. Invest. 109, 849–855 (2002).
Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).
Bourajjaj, M. et al. NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure. J. Biol. Chem. 283, 22295–22303 (2008).
Wilkins, B. J. et al. Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol. Cell Biol. 22, 7603–7613 (2002).
De Windt, L. J. et al. Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc. Natl Acad. Sci. USA 98, 3322–3327 (2001).
Hogan, P. G., Chen, L., Nardone, J. & Rao, A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17, 2205–2232 (2003).
De Windt, L. J. et al. Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo: An apoptosis-independent model of dilated heart failure. Circ. Res. 86, 255–263 (2000).
Rockman, H. A. et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc. Natl Acad. Sci. USA 88, 8277–8281 (1991).
Arron, J. R. et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441, 595–600 (2006).
Gwack, Y. et al. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441, 646–650 (2006).
Crabtree, G. R. & Olson, E. N. NFAT signaling: choreographing the social lives of cells. Cell 109, S67–S79 (2002).
Fotaki, V. et al. Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol. Cell Biol. 22, 6636–6647 (2002).
Krutzfeldt, J. et al. Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res. 35, 2885–2892 (2007).
Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).
Kuhn, C. et al. DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy. J. Biol. Chem. 284, 17320–17327 (2009).
Rothermel, B. A. et al. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc. Natl Acad. Sci. USA 98, 3328–3333 (2001).
van Rooij, E. et al. MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction. Circ. Res. 94, e18–e26 (2004).
Rybkin, I. I. et al. Conditional expression of SV40 T-antigen in mouse cardiomyocytes facilitates an inducible switch from proliferation to differentiation. J. Biol. Chem. 278, 15927–15934 (2003).
De Windt, L. J., Lim, H. W., Haq, S., Force, T. & Molkentin, J. D. Calcineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart. Cross-talk between cardiac hypertrophic signaling pathways. J. Biol. Chem. 275, 13571–13579 (2000).
He, T. C. et al. A simplified system for generating recombinant adenoviruses. Proc. Natl Acad. Sci. USA 95, 2509–2514 (1998).
Gurda, G. T., Guo, L., Lee, S. H., Molkentin, J. D. & Williams, J. A. Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo. Mol. Biol. Cell 19, 198–206 (2008).
Acknowledgements
We gratefully acknowledge T. Seidler and J. Molkentin for adenoviruses; R. Hesdahl and D. Bogaert for logistical and technical support; and members of the De Windt laboratory for technical support and helpful discussions. P.D.C.M. was supported by a Heart Failure Association Research Fellowship from the European Society of Cardiology. L.D.W. was supported by grants 912-04-054, 912-04-017 and a VIDI award 917-863-72 from the Netherlands Organization for Health Research and Development and the Netherlands Heart Foundation program grant NHS2007B167. G.C. and L.D.W were supported by the Fondation Leducq Transatlantic Network of Excellence program 08-CVD-03.
Author information
Authors and Affiliations
Contributions
P.D.C.M, K.S., M.G., A.S., S.L., H.A., A.H., M.B., R.N., J.K and L.D.W. performed the experiments; P.D.C.M, K.S., M.G., A.S., C.C., M.A., T.E. and L.D.W. analysed the data; P.D.C.M., K.S. and L.D.W designed the study; P.D.C.M, K.S. and L.D.W. wrote the manuscript; P.D.C.M. and K.S. contributed equally as joint first authors.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
Supplementary Information (PDF 1687 kb)
Rights and permissions
About this article
Cite this article
da Costa Martins, P., Salic, K., Gladka, M. et al. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nat Cell Biol 12, 1220–1227 (2010). https://doi.org/10.1038/ncb2126
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb2126
This article is cited by
-
Circular RNA has Circ 001372-Reduced Inflammation in Ovalbumin-Induced Asthma Through Sirt1/NFAT5 Signaling Pathway by miRNA-128-3p
Molecular Biotechnology (2022)
-
Molecular study of the proliferation process of beta cells derived from pluripotent stem cells
Molecular Biology Reports (2022)
-
DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis
Cellular and Molecular Life Sciences (2021)
-
A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration
Nature Communications (2021)
-
Coupled feedback regulation of nuclear factor of activated T-cells (NFAT) modulates activation-induced cell death of T cells
Scientific Reports (2019)