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

• Published in: Basic research in cardiology 2021-12, Vol.116 (1), p.16-16, Article 16
• Main Authors: Lassen, Thomas Ravn, Just, Jesper, Hjortbak, Marie Vognstoft, Jespersen, Nichlas Riise, Stenz, Katrine Tang, Gu, Tingting, Yan, Yan, Su, Junyi, Hansen, Jakob, Bæk, Rikke, Jørgensen, Malene Møller, Nyengaard, Jens Randel, Kristiansen, Steen Buus, Drasbek, Kim Ryun, Kjems, Jørgen, Bøtker, Hans Erik
• Format: Article
• Language: English
• Subjects: Animals; Arm - blood supply; Cardiology; Cell survival; Conditioning; Disease Models, Animal; Extracellular vesicles; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; Extracellular Vesicles - transplantation; Gene Expression Regulation; Healthy Volunteers; Humans; Injuries; Ischemia; Ischemic Preconditioning; Isolated Heart Preparation; Male; Medicine; Medicine & Public Health; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocardium; Myocardium - metabolism; Myocardium - pathology; Non-coding RNA; Original Contribution; Plasma; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion; Rodents; Size exclusion chromatography; TOR protein; Vesicles
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-021-00856-w

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.