Thomas Ravn Lassen1,2, Jesper Just3, Marie Vognstoft Hjortbak4,5, Nichlas Riise Jespersen4,5, Katrine Tang Stenz3,6, Tingting Gu3, Yan Yan7, Junyi Su7, Jakob Hansen8, Rikke Bæk9, Malene Møller Jørgensen9,10, Jens Randel Nyengaard5,11,12, Steen Buus Kristiansen4, Kim Ryun Drasbek3,6, Jørgen Kjems7,13, Hans Erik Bøtker4,5. 1. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. thomasravnl@clin.au.dk. 2. Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. thomasravnl@clin.au.dk. 3. Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark. 4. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. 5. Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. 6. Sino-Danish Center for Research and Education, Beijing, China. 7. Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark. 8. Department of Forensic Medicine, Aarhus University, Aarhus, Denmark. 9. Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark. 10. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. 11. Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Aarhus, Denmark. 12. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark. 13. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
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.
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.
Authors: Hans Erik Bøtker; Derek Hausenloy; Ioanna Andreadou; Salvatore Antonucci; Kerstin Boengler; Sean M Davidson; Soni Deshwal; Yvan Devaux; Fabio Di Lisa; Moises Di Sante; Panagiotis Efentakis; Saveria Femminò; David García-Dorado; Zoltán Giricz; Borja Ibanez; Efstathios Iliodromitis; Nina Kaludercic; Petra Kleinbongard; Markus Neuhäuser; Michel Ovize; Pasquale Pagliaro; Michael Rahbek-Schmidt; Marisol Ruiz-Meana; Klaus-Dieter Schlüter; Rainer Schulz; Andreas Skyschally; Catherine Wilder; Derek M Yellon; Peter Ferdinandy; Gerd Heusch Journal: Basic Res Cardiol Date: 2018-08-17 Impact factor: 17.165
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Authors: K Brennan; K Martin; S P FitzGerald; J O'Sullivan; Y Wu; A Blanco; C Richardson; M M Mc Gee Journal: Sci Rep Date: 2020-01-23 Impact factor: 4.379
Authors: Tingting Gu; Jesper Just; Katrine Tang Stenz; Yan Yan; Peter Sieljacks; Jakob Wang; Thomas Skjaerlund Groennebaek; Jesper Emil Jakobsgaard; Emil Rindom; Jon Herskind; Anders Gravholt; Thomas Ravn Lassen; Mathias Jørgensen; Rikke Bæk; Eugenio Gutiérrez-Jiménez; Nina Kerting Iversen; Peter Mondrup Rasmussen; Jens Randel Nyengaard; Malene Møller Jørgensen; Frank de Paoli; Hans Erik Bøtker; Jørgen Kjems; Kristian Vissing; Kim Ryun Drasbek Journal: Int J Mol Sci Date: 2022-03-19 Impact factor: 5.923