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      Extracellular vesicles isolated from patients undergoing remote ischemic preconditioning decrease hypoxia-evoked apoptosis of cardiomyoblasts after isoflurane but not propofol exposure

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          Abstract

          Remote ischemic preconditioning (RIPC) can evoke cardioprotection following ischemia/reperfusion and this may depend on the anesthetic used. We tested whether 1) extracellular vesicles (EVs) isolated from humans undergoing RIPC protect cardiomyoblasts against hypoxia-induced apoptosis and 2) this effect is altered by cardiomyoblast exposure to isoflurane or propofol. EVs were isolated before and 60 min after RIPC or Sham from ten patients undergoing coronary artery bypass graft surgery with isoflurane anesthesia and quantified by Nanoparticle Tracking Analysis. Following EV-treatment for 6 hours under exposure of isoflurane or propofol, rat H9c2 cardiomyoblasts were cultured for 18 hours in normoxic or hypoxic atmospheres. Apoptosis was detected by flow cytometry. Serum nanoparticle concentrations in patients had increased sixty minutes after RIPC compared to Sham (2.5x10 11±4.9x10 10 nanoparticles/ml; Sham: 1.2x10 11±2.0x10 10; p = 0.04). Hypoxia increased apoptosis of H9c2 cells (hypoxia: 8.4%±0.6; normoxia: 2.5%±0.1; p<0.0001). RIPC-EVs decreased H9c2 cell apoptosis compared to control (apoptotic ratio: 0.83; p = 0.0429) while Sham-EVs showed no protection (apoptotic ratio: 0.97). Prior isoflurane exposure in vitro even increased protection (RIPC-EVs/control, apoptotic ratio: 0.79; p = 0.0035; Sham-EVs/control, apoptotic ratio:1.04) while propofol (50μM) abrogated protection by RIPC-EVs (RIPC-EVs/control, Apoptotic ratio: 1.01; Sham-EVs/control, apoptotic ratio: 0.94; p = 0.602). Thus, EVs isolated from patients undergoing RIPC under isoflurane anesthesia protect H9c2 cardiomyoblasts against hypoxia-evoked apoptosis and this effect is abrogated by propofol. This supports a role of human RIPC-generated EVs in cardioprotection and underlines propofol as a possible confounder in RIPC-signaling mediated by EVs.

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          Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4

          J. Xiao, Y. Y. Pan, X. Li … (2016)
          Cardiac progenitor cells derived from adult heart have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are known to mediate cell–cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we investigated the cardiac progenitor cell (CPC)-derived exosomal miRNAs on protecting myocardium under oxidative stress. Sca1+CPCs-derived exosomes were purified from conditional medium, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting using CD63, CD9 and Alix as markers. Exosomes production was measured by NTA, the result showed that oxidative stress-induced CPCs secrete more exosomes compared with normal condition. Although six apoptosis-related miRNAs could be detected in two different treatment-derived exosomes, only miR-21 was significantly upregulated in oxidative stress-induced exosomes compared with normal exosomes. The same oxidative stress could cause low miR-21 and high cleaved caspase-3 expression in H9C2 cardiac cells. But the cleaved caspase-3 was significantly decreased when miR-21 was overexpressed by transfecting miR-21 mimic. Furthermore, miR-21 mimic or inhibitor transfection and luciferase activity assay confirmed that programmed cell death 4 (PDCD4) was a target gene of miR-21, and miR-21/PDCD4 axis has an important role in anti-apoptotic effect of H9C2 cell. Western blotting and Annexin V/PI results demonstrated that exosomes pre-treated H9C2 exhibited increased miR-21 whereas decreased PDCD4, and had more resistant potential to the apoptosis induced by the oxidative stress, compared with non-treated cells. These findings revealed that CPC-derived exosomal miR-21 had an inhibiting role in the apoptosis pathway through downregulating PDCD4. Restored miR-21/PDCD4 pathway using CPC-derived exosomes could protect myocardial cells against oxidative stress-related apoptosis. Therefore, exosomes could be used as a new therapeutic vehicle for ischemic cardiac disease.
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            Roles of exosomes in cardioprotection.

            Lucio Barile, Tiziano Moccetti, Eduardo Marbán … (2017)
            Exosomes are extracellular vesicles of endosomal origin which have emerged as key mediators of intercellular communication. All major cardiac cell types-including cardiomyocytes, endothelial cells, and fibroblasts-release exosomes that modulate cellular functions. Exosomes released from human cardiac progenitor cells (CPCs) are cardioprotective and improve cardiac function after myocardial infarction to an extent comparable with that achieved by their parent cells. Cardiac progenitor cell-derived exosomes are enriched in cardioprotective microRNAs, particularly miR-146a-3p. Circulating exosomes mediate remote ischaemic preconditioning. Moreover, they currently are being investigated as diagnostic markers. The discovery that cell-derived extracellular signalling organelles mediate the paracrine effects of stem cells suggests that cell-free strategies could supplant cell transplantation. This review discusses emerging roles of exosomes in cardiovascular physiology, with a focus on cardioprotective activities of CPC-derived exosomes.
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              Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA‐21

              Kan Wang, Zhi Nong Jiang, Keith A Webster … (2016)
              Abstract Our group recently reported positive therapeutic benefit of human endometrium‐derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose‐derived MSCs (AdMSCs) were characterized by fluorescence‐activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR‐21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR‐21 by anti‐miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR‐21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR‐21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. Stem Cells Translational Medicine 2017;6:209–222
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                Author and article information

                Contributors
                Frederik Abel:
                ORCID: http://orcid.org/0000-0001-8988-6917
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Florian Murke: Role: InvestigationRole: Methodology
                Morten Gaida: Role: Investigation
                Nicolas Garnier: Role: Investigation
                Crista Ochsenfarth: Role: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draft
                Carsten Theiss: Role: InvestigationRole: Writing – original draft
                Matthias Thielmann: Role: Data curationRole: Methodology
                Petra Kleinbongard: Role: MethodologyRole: Writing – review & editing
                Bernd Giebel: Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Jürgen Peters: Role: Formal analysisRole: Writing – review & editing
                Ulrich H. Frey: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Meijing Wang: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 14 February 2020
                Publication date Collection: 2020
                Volume: 15
                Issue: 2
                Electronic Location Identifier: e0228948
                Affiliations
                [1 ] Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum Essen, Essen, Germany
                [2 ] Institut für Transfusionsmedizin, Universität Duisburg-Essen & Universitätsklinikum Essen, Essen, Germany
                [3 ] Klinik für Anästhesiologie, Operative Intensivmedizin, Schmerz- und Palliativmedizin, Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum, Bochum, Germany
                [4 ] Institut für Anatomie, Abteilung für Cytologie, Ruhr-Universität-Bochum, Bochum, Germany
                [5 ] Klinik für Thorax- und Kardiovaskuläre Chirurgie, Universität Duisburg-Essen & Universitätsklinikum Essen, Essen, Germany
                [6 ] Institut für Pathophysiologie, Universität Duisburg-Essen & Universitätsklinikum Essen, Essen, Germany
                Indiana University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-8988-6917
                Article
                Publisher ID: PONE-D-19-25675
                DOI: 10.1371/journal.pone.0228948
                PMC ID: 7021285
                PubMed ID: 32059016
                SO-VID: c2e63404-bb04-4b84-b8cd-081b1d620873
                Copyright © © 2020 Abel et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 12 September 2019
                Date accepted : 26 January 2020
                Page count
                Figures: 7, Tables: 1, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003042, Else Kröner-Fresenius-Stiftung;
                Award ID: 8000 Euro
                Award Recipient :
                This work was supported by Else Kröner-Fresenius-Stiftung. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Death
                Subject: Apoptosis
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Hypoxia
                Subject: Medicine and Health Sciences
                Subject: Anesthesiology
                Subject: Anesthesia
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Anesthesia
                Subject: Medicine and Health Sciences
                Subject: Surgical and Invasive Medical Procedures
                Subject: Cardiovascular Procedures
                Subject: Coronary Artery Bypass Grafting
                Subject: Research and Analysis Methods
                Subject: Microscopy
                Subject: Light Microscopy
                Subject: Fluorescence Microscopy
                Subject: Physical Sciences
                Subject: Materials Science
                Subject: Materials
                Subject: Mixtures
                Subject: Colloids
                Subject: Emulsions
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Drugs
                Subject: Anesthetics
                Subject: Medicine and Health Sciences
                Subject: Pain Management
                Subject: Anesthetics
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Structures and Organelles
                Subject: Vesicles
                Subject: Exosomes
                Custom metadata
                Data Availability All relevant data are within the manuscript and its Supporting Information files.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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