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Abstract

Ageing is the predominant risk factor for cardiovascular diseases1 and contributes to a significantly worse outcome in patients with acute myocardial infarction2. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing3,4. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

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Change history

  • 08 March 2013

    The first Supplementary Information file has been replaced with an updated version.

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Gene Expression Omnibus

Data deposits

Data are available at the National Center for Biotechnology Information Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE43556.

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Acknowledgements

We thank M. Muhly-Reinholz, A. Knau, B. Zimmermann, N. Reinfeld and F. Gehring for technical assistance, F. W. Alt for providing SIRT1 mutant mice and D. Sassoon and G. Marazzi for conceptual advice. R.A.B. was supported by the Netherlands Organization for Scientific Research (NWO) and K.I. by a Research Grant Abroad of the Japanese Heart Foundation. This study was supported by a start-(Exc 147-1) to R.A.B., by the European Research Council (Advanced grant “Angiomirs”) and the German Center for Cardiovascular Research DZHK and the European Union FP7 project Endostem (Grant no. 241440) to S.D. H.A.K. and O.J.M. are supported by the German Centre for Cardiovascular Research (DZHK) and by the German Ministry of Education and Research (BMBF). M.P. is supported by the Max Planck Society, the Fondation Leducq (ARTEMIS) and an ERC Starting Grant (ANGIOMET). H.H. is supported by the DFG, the Deutsche Krebshilfe and the Rudolf-Bartling-Stiftung.

Author information

Author notes

    • Reinier A. Boon
    •  & Kazuma Iekushi

    These authors contributed equally to this work.

    • Michael Potente

    Present address: Max-Planck-Institute for Heart and Lung Reseach, 61231 Bad Nauheim, Germany.

Affiliations

  1. Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany

    • Reinier A. Boon
    • , Kazuma Iekushi
    • , Timon Seeger
    • , Ariane Fischer
    • , Susanne Heydt
    • , David Kaluza
    • , Karine Tréguer
    • , Guillaume Carmona
    • , Angelika Bonauer
    • , Michael Potente
    •  & Stefanie Dimmeler
  2. Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, 80337 Munich, Germany

    • Stefanie Lechner
    •  & Heiko Hermeking
  3. Department of Cardiology, Internal Medicine III, Goethe University, 60590 Frankfurt, Germany

    • Timon Seeger
    • , Zenawit Girmatsion
    • , Peter Biliczki
    • , Joachim R. Ehrlich
    • , Michael Potente
    •  & Andreas M. Zeiher
  4. Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081BT Amsterdam, the Netherlands

    • Anton J. G. Horrevoets
  5. Myology Group, UMR S787 INSERM, Université Pierre et Marie Curie Paris VI, Institut de Myologie, Pitie-Salpétrière, Paris Cedex, France

    • Nathalie Didier
  6. Internal Medicine III, Heidelberg Universiy Hospital, 69120 Heidelberg, Germany

    • Hugo A. Katus
    •  & Oliver J. Müller
  7. German Center for Cardiovascular Research DZHK, 13347 Berlin, Germany

    • Hugo A. Katus
    • , Oliver J. Müller
    • , Andreas M. Zeiher
    •  & Stefanie Dimmeler

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Contributions

R.A.B. designed and performed experiments, analysed data and wrote the manuscript. S.L. and H.H. generated the miR-34a−/− mice. K.I., T.S., A.F., S.H., D.K., K.T., G.C. and A.B. performed experiments and analysed data. A.J.G.H. analysed microarray data. N.D., Z.G., P.B., J.R.E. and M.P. provided essential materials. H.A.K. and O.J.M. developed the AAV vectors. A.M.Z. wrote the manuscript. S.D. designed experiments, analysed data and wrote the manuscript. All authors have proofread the manuscript.

Competing interests

R.A.B., S.D. and A.M.Z. applied for a patent regarding this work.

Corresponding author

Correspondence to Stefanie Dimmeler.

Supplementary information

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    Supplementary Information

    This file contains Supplementary Figures 1-16. This file was replaced on 8 March 2013.

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    Supplementary Tables

    This file contains Supplementary Tables 1-4.

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DOI

https://doi.org/10.1038/nature11919

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