Letter | Published:

Inhibition of miR-25 improves cardiac contractility in the failing heart

Nature volume 508, pages 531535 (24 April 2014) | Download Citation

Subjects

Abstract

Heart failure is characterized by a debilitating decline in cardiac function1, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy2,3. MicroRNAs (miRNAs) are dysregulated in heart failure4,5 but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.

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Acknowledgements

We thank P. Aza-Blanc and F. Cerignoli; O. Kim, L. Liang and E. Kohlbrenner for their technical support; G. Christensen for providing the SERCA2a knockout mice; and H. el Azzouzi for TAC operations and histological sections. This work was supported by California Institute for Regenerative Medicine (RC1-000132), the National Institutes of Health (NIH) (R01HL113601, P01HL098053 and R01HL108176) and the Fondation Leducq to M.M.; by the NIH (NIH R01HL093183, R01HL088434, P20HL100396 and a Program of Excellence in Nanotechnology Contract no. HHSN26820100045C and P50HL112324) to R.J.H.; P30CA030199 and P30AR061303 for Sanford-Burnham Medical Research Institute functional genomics and cytometry. W.J.P. was supported by the Global Research Laboratory Program of the South Korean Government (M6-0605-00-0001). J.P.G.S. and P.A.F.D. were supported by the Netherlands Heart foundation and Project P1.05 LUST of the BioMedical Materials institute co-funded by the Dutch Ministry of Economic Affairs, Agriculture and Innovation. C.W. was supported by a fellowship from the Spanish National Research Council. A.v.M. was a Netherlands Heart Institute ICIN fellow.

Author information

Author notes

    • Christine Wahlquist
    •  & Dongtak Jeong

    These authors contributed equally to this work.

Affiliations

  1. Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA

    • Christine Wahlquist
    • , Agustin Rojas-Muñoz
    • , Alain van Mil
    •  & Mark Mercola
  2. The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Dongtak Jeong
    • , Changwon Kho
    • , Ahyoung Lee
    • , Shinichi Mitsuyama
    •  & Roger J. Hajjar
  3. Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands

    • Alain van Mil
    • , Joost P. G. Sluijter
    •  & Pieter A. F. Doevendans
  4. Global Research Laboratory, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, South Korea

    • Woo Jin Park

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Contributions

C.W., A.R.-M., D.J., R.J.H. and M.M. conceived and designed the project following an initial concept from M.M.; C.W., D.J., A.R.-M., C.K., A.L., S.M. and A.v.M. performed experiments and analysed the data; and interpreted results with M.M. and R.J.H. W.J.P. developed reagents for post-translational modification assays on SERCA2a. M.M., R.J.H., C.W., A.R.-M., D.J., A.v.M., P.A.F.D. and J.P.G.S. wrote and edited the manuscript. Major funding was obtained by P.A.F.D., R.J.H. and M.M.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mark Mercola.

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DOI

https://doi.org/10.1038/nature13073

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