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Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles

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Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Background

Remote ischemic conditioning (RIC) by brief periods of limb ischemia and reperfusion protects against ischemia–reperfusion injury. We studied the cardioprotective role of extracellular vesicles (EV)s released into the circulation after RIC and EV accumulation in injured myocardium.

Methods

We used plasma from healthy human volunteers before and after RIC (pre-PLA and post-PLA) to evaluate the transferability of RIC. Pre- and post-RIC plasma samples were separated into an EV enriched fraction (pre-EV + and post-EV +) and an EV poor fraction (pre-EV- and post-EV-) by size exclusion chromatography. Small non-coding RNAs from pre-EV + and post-EV + were purified and profiled by NanoString Technology. Infarct size was compared in Sprague–Dawley rat hearts perfused with isolated plasma and fractions in a Langendorff model. In addition, fluorescently labeled EVs were used to assess homing in an in vivo rat model. (ClinicalTrials.gov, number: NCT03380663)

Results

Post-PLA reduced infarct size by 15% points compared with Pre-PLA (55 ± 4% (n = 7) vs 70 ± 6% (n = 8), p = 0.03). Post-EV + reduced infarct size by 16% points compared with pre-EV + (53 ± 15% (n = 13) vs 68 ± 12% (n = 14), p = 0.03). Post-EV- did not affect infarct size compared to pre-EV- (64 ± 3% (n = 15) and 68 ± 10% (n = 16), p > 0.99). Three miRNAs (miR-16-5p, miR-144-3p and miR-451a) that target the mTOR pathway were significantly up-regulated in the post-EV + group. Labelled EVs accumulated more intensely in the infarct area than in sham hearts.

Conclusion

Cardioprotection by RIC can be mediated by circulating EVs that accumulate in injured myocardium. The underlying mechanism involves modulation of EV miRNA that may promote cell survival during reperfusion.

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Acknowledgements

We thank Casper Carlsen Elkjær for excellent technical assistance.

Funding

This study is supported by the Danish Council for Strategic Research (11‐115818), the Independent Research Fund Denmark (11‐108354), the Novo Nordisk Foundation (NNF14OC0013337 and NNF 15OC0016674), TrygFonden (109624), and the European Union Cost Action (CA16225).

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Authors and Affiliations

  1. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

    Thomas Ravn Lassen, Marie Vognstoft Hjortbak, Nichlas Riise Jespersen, Steen Buus Kristiansen & Hans Erik Bøtker

  2. Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark

    Thomas Ravn Lassen, Marie Vognstoft Hjortbak, Nichlas Riise Jespersen, Jens Randel Nyengaard & Hans Erik Bøtker

  3. Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark

    Jesper Just, Katrine Tang Stenz, Tingting Gu & Kim Ryun Drasbek

  4. Sino-Danish Center for Research and Education, Beijing, China

    Katrine Tang Stenz & Kim Ryun Drasbek

  5. Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark

    Yan Yan, Junyi Su & Jørgen Kjems

  6. Department of Forensic Medicine, Aarhus University, Aarhus, Denmark

    Jakob Hansen

  7. Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark

    Rikke Bæk & Malene Møller Jørgensen

  8. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Malene Møller Jørgensen

  9. Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Aarhus, Denmark

    Jens Randel Nyengaard

  10. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark

    Jens Randel Nyengaard

  11. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

    Jørgen Kjems

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  1. Thomas Ravn Lassen
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  2. Jesper Just
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Contributions

Conceptualization: TRL and HEB; Methodology: TRL, JJ, NRJ, MVH, TG, YY, JK and HEB; Investigation: TRL, JJ, NRJ, MVH, KTS, TG, YY, JS, JRN, JH, MMJ, RB; Writing—Original Draft: TRL and HEB; Writing—review and Editing: TRL, JJ, NRJ, MVH, KTS, TG, YY, JS, JH, JRN, KRD, SBK, JK, MMJ and HEB; Funding Acquisition: HEB, JK and KRD; Resources: HEB, JRN, JK and KRD; Supervision: HEB, JK, SBK.

Corresponding author

Correspondence to Thomas Ravn Lassen.

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The authors declare no competing interests.

Ethical approval

This study was performed in line with the principals of the Helsinki declaration. Experiments conformed to Danish law (act. no. 1306 of 23/11/2007) and institutional guidelines for animal research. Additionally, the study was approved by the Danish ethical research committee (M-2016–218-16) and registered at clinicaltrials.gov (reg: NCT03380663).

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All healthy volunteers signed a written consent to participate in the study after a written and oral description of the study and its purpose.

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Individuals signed informed consent regarding publication of their data.

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Lassen, T.R., Just, J., Hjortbak, M.V. et al. Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles. Basic Res Cardiol 116, 16 (2021). https://doi.org/10.1007/s00395-021-00856-w

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