Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure

  1. Andrea Ruiz-Velasco
  2. Min Zi
  3. Susanne S Hille
  4. Tayyiba Azam
  5. Namrita Kaur
  6. Juwei Jiang
  7. Binh Nguyen
  8. Karolina Sekeres
  9. Pablo Binder
  10. Lucy Collins
  11. Fay Pu
  12. Han Xiao
  13. Kaomei Guan
  14. Norbert Frey
  15. Elizabeth J Cartwright
  16. Oliver J Müller  Is a corresponding author
  17. Xin Wang  Is a corresponding author
  18. Wei Liu  Is a corresponding author
  1. The University of Manchester, United Kingdom
  2. University of Kiel, Germany
  3. Technische Universität Dresden, Germany
  4. University of Edinburgh, United Kingdom
  5. Peking University, China

Abstract

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

  1. Andrea Ruiz-Velasco

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Min Zi

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Susanne S Hille

    Department of Internal Medicine III, University of Kiel, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Tayyiba Azam

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Namrita Kaur

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Juwei Jiang

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Binh Nguyen

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Karolina Sekeres

    Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Pablo Binder

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Lucy Collins

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Fay Pu

    Edinburgh University Medical School, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Han Xiao

    Institute of Vascular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Kaomei Guan

    Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Norbert Frey

    Clinic for Internal Medicine III, Cardiology and Angiology, University of Kiel, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Elizabeth J Cartwright

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Oliver J Müller

    Department of Internal Medicine III, University of Kiel, Kiel, Germany
    For correspondence
    Oliver.Mueller@uksh.de
    Competing interests
    The authors declare that no competing interests exist.
  17. Xin Wang

    Faculty of Life Science, The University of Manchester, Manchester, United Kingdom
    For correspondence
    xin.wang@manchester.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  18. Wei Liu

    Division of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom
    For correspondence
    wei.liu@manchester.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1592-6693

Funding

British Heart Foundation (FS/15/16/31477)

  • Wei Liu

British Heart Foundation (FS/18/73/33973)

  • Wei Liu

British Heart Foundation (PG/12/76/29852)

  • Xin Wang

British Heart Foundation (PG/14/71/310)

  • Xin Wang

British Heart Foundation (PG/14/70/3103)

  • Xin Wang

German Centre for Cardiovascular Research (81Z0700201)

  • Oliver J Müller

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal studies were performed in accordance with the United Kingdom Animals (Scientific Procedures) Act 1986 under the Home Office license P3A97F3D1, and were approved by the University of Manchester Ethics Committee.

Reviewing Editor

  1. Milica Radisic, University of Toronto, Canada

Version history

  1. Received: December 9, 2019
  2. Accepted: March 27, 2020
  3. Accepted Manuscript published: March 30, 2020 (version 1)
  4. Version of Record published: April 3, 2020 (version 2)

Copyright

© 2020, Ruiz-Velasco et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Andrea Ruiz-Velasco
  2. Min Zi
  3. Susanne S Hille
  4. Tayyiba Azam
  5. Namrita Kaur
  6. Juwei Jiang
  7. Binh Nguyen
  8. Karolina Sekeres
  9. Pablo Binder
  10. Lucy Collins
  11. Fay Pu
  12. Han Xiao
  13. Kaomei Guan
  14. Norbert Frey
  15. Elizabeth J Cartwright
  16. Oliver J Müller
  17. Xin Wang
  18. Wei Liu
(2020)
Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure
eLife 9:e54298.
https://doi.org/10.7554/eLife.54298

Share this article

https://doi.org/10.7554/eLife.54298

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    Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.

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    Funding:

    This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.