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

Thomas Ravn Lassen; Jesper Just; Marie Vognstoft Hjortbak; Nichlas Riise Jespersen; Katrine Tang Stenz; Tingting Gu; Yan Yan; Junyi Su; Jakob Hansen; Rikke Bæk; Malene Møller Jørgensen; Jens Randel Nyengaard; Steen Buus Kristiansen; Kim Ryun Drasbek; Jørgen Kjems; Hans Erik Bøtker

doi:10.1007/s00395-021-00856-w

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

Thomas Ravn Lassen^*, Jesper Just, Marie Vognstoft Hjortbak, Nichlas Riise Jespersen, Katrine Tang Stenz, Tingting Gu, Yan Yan, Junyi Su, Jakob Hansen, Rikke Bæk, Malene Møller Jørgensen, Jens Randel Nyengaard, Steen Buus Kristiansen, Kim Ryun Drasbek, Jørgen Kjems, Hans Erik Bøtker

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Article number	16
Journal	Basic Research in Cardiology
Volume	116
Issue	1
Number of pages	18
ISSN	0300-8428
DOIs	https://doi.org/10.1007/s00395-021-00856-w
Publication status	Published - Mar 2021

Keywords

Cardioprotection
Extracellular vesicles
Ischemia/reperfusion
MiRNA
Myocardial Infarction
Remote ischemic conditioning

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10.1007/s00395-021-00856-w

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Lassen, T. R., Just, J., Hjortbak, M. V., Jespersen, N. R., Stenz, K. T., Gu, T., Yan, Y., Su, J., Hansen, J., Bæk, R., Jørgensen, M. M., Nyengaard, J. R., Kristiansen, S. B., Drasbek, K. R., Kjems, J., & Bøtker, H. E. (2021). Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles. Basic Research in Cardiology, 116(1), Article 16. https://doi.org/10.1007/s00395-021-00856-w

@article{ba54b3d007334d0a8b41664d013242d8,

title = "Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles",

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.",

keywords = "Cardioprotection, Extracellular vesicles, Ischemia/reperfusion, MiRNA, Myocardial Infarction, Remote ischemic conditioning",

author = "Lassen, {Thomas Ravn} and Jesper Just and Hjortbak, {Marie Vognstoft} and Jespersen, {Nichlas Riise} and Stenz, {Katrine Tang} and Tingting Gu and Yan Yan and Junyi Su and Jakob Hansen and Rikke B{\ae}k and J{\o}rgensen, {Malene M{\o}ller} and Nyengaard, {Jens Randel} and Kristiansen, {Steen Buus} and Drasbek, {Kim Ryun} and J{\o}rgen Kjems and B{\o}tker, {Hans Erik}",

note = "Funding Information: We thank Casper Carlsen Elkj?r for excellent technical assistance. Publisher Copyright: {\textcopyright} 2021, Springer-Verlag GmbH Germany, part of Springer Nature. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = mar,

doi = "10.1007/s00395-021-00856-w",

language = "English",

volume = "116",

journal = "Basic Research in Cardiology",

issn = "0300-8428",

publisher = "Springer Medizin",

number = "1",

}

Lassen, TR , Just, J, Hjortbak, MV, Jespersen, NR , Stenz, KT, Gu, T, Yan, Y, Su, J, Hansen, J, Bæk, R, Jørgensen, MM, Nyengaard, JR , Kristiansen, SB , Drasbek, KR , Kjems, J & Bøtker, HE 2021, 'Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles', Basic Research in Cardiology, vol. 116, no. 1, 16. https://doi.org/10.1007/s00395-021-00856-w

Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles. / Lassen, Thomas Ravn ; Just, Jesper; Hjortbak, Marie Vognstoft et al.
In: Basic Research in Cardiology, Vol. 116, No. 1, 16, 03.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles

AU - Lassen, Thomas Ravn

AU - Just, Jesper

AU - Hjortbak, Marie Vognstoft

AU - Jespersen, Nichlas Riise

AU - Stenz, Katrine Tang

AU - Gu, Tingting

AU - Yan, Yan

AU - Su, Junyi

AU - Hansen, Jakob

AU - Bæk, Rikke

AU - Jørgensen, Malene Møller

AU - Nyengaard, Jens Randel

AU - Kristiansen, Steen Buus

AU - Drasbek, Kim Ryun

AU - Kjems, Jørgen

AU - Bøtker, Hans Erik

N1 - Funding Information: We thank Casper Carlsen Elkj?r for excellent technical assistance. Publisher Copyright: © 2021, Springer-Verlag GmbH Germany, part of Springer Nature. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

KW - Cardioprotection

KW - Extracellular vesicles

KW - Ischemia/reperfusion

KW - MiRNA

KW - Myocardial Infarction

KW - Remote ischemic conditioning

UR - http://www.scopus.com/inward/record.url?scp=85102380430&partnerID=8YFLogxK

U2 - 10.1007/s00395-021-00856-w

DO - 10.1007/s00395-021-00856-w

M3 - Journal article

C2 - 33689033

AN - SCOPUS:85102380430

SN - 0300-8428

VL - 116

JO - Basic Research in Cardiology

JF - Basic Research in Cardiology

IS - 1

M1 - 16

ER -

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

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Keywords

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