title: Exosomal miR-142-3p is increased during cardiac allograft rejection and augments vascular permeability through down-regulation of endothelial RAB11FIP2 expression.
abstract: OBJECTIVE
  Exosome-mediated microRNA transfer is a recently discovered mode of cell-to-cell communication, in which microRNAs act as paracrine molecules, exerting their regulatory effects in recipient cells. T cells and endothelial cells are two main players in the mechanism of acute cellular cardiac rejection. The aim of this study was to investigate the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for the molecular mechanisms that drive acute cellular rejection in heart transplantation.
  
  
  RESULTS
  Exosomes isolated from serum samples of heart transplant patients with and without acute cardiac allograft rejection were profiled and showed enrichment of miR-142-3p, miR-92a-3p, miR-339-3p and miR-21-5p. Treatment of endothelial cells with the respected serum exosomes resulted the increased of miR-142-3p level in endothelial cells. Using T cells isolated from healthy donors and activated with either anti-CD3/CD28 antibody or IL-2/PHA, we could show that miR-142-3p is released from activated cells, is contained in exosomes and can be transferred to human vascular endothelial cells in vitro. Transcriptome analysis of endothelial cells treated with activated T cell supernatant with or without exosomes was used to identify mRNA targets of transferred miR-142-3-p. Overexpression of miR-142-3p in endothelial cells resulted in a significant down-regulation of RAB11FIP2, and interaction of miR-142-3p with its predicted target site was confirmed with a reporter assay. Moreover, treatment of endothelial cells with serum exosomes from heart transplant patients with acute cellular rejection resulted in down-regulation of RAB11FIP2 expression and increase in vascular endothelial permeability.
  
  
  CONCLUSIONS
  We have identified a novel mechanism whereby miR-142-3p, a microRNA enriched in exosomes during acute cellular rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of RAB11FIP2. This study sheds new light on the interaction between host immune system and cardiac allograft endothelium during acute cellular rejection.
authors.affiliation: Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden.
authors.forename: Ihdina
authors.initials: I
authors.lastname: Sukma Dewi
authors.affiliation: Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden.
authors.forename: Selvi
authors.initials: S
authors.lastname: Celik
authors.affiliation: Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.affiliation: Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.|UBC James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Hollander
authors.affiliation: Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Lam
authors.affiliation: netCAD, Canadian Blood Services, 2150 Western Parkway, Vancouver, British Columbia V6T 1V6, Canada.
authors.forename: Janet-Wilson
authors.initials: JW
authors.lastname: McManus
authors.affiliation: Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.|UBC James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.|Department of Medicine, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.|Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Tebbutt
authors.affiliation: Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.|Department of Computer Science, University of British Columbia, 2366 Main Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Ng
authors.affiliation: Vancouver General Hospital, 899 West 12th Avenue, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Keown
authors.affiliation: Department of Transplantation and Immunology, Vancouver Coastal Health Research Institute, 910 West 10th Avenue, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: McMaster
authors.affiliation: Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.|UBC James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.|Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Bruce
authors.initials: B
authors.lastname: McManus
authors.affiliation: Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Öhman
authors.affiliation: Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Gidlöf
mesh_terms: D020413:3' Untranslated Regions; D000208:Acute Disease; D000328:Adult; D000368:Aged; D064591:Allografts; D001665:Binding Sites; D002199:Capillary Permeability; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D015536:Down-Regulation; D055354:Exosomes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D019899:Paracrine Communication; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D020691:rab GTP-Binding Proteins
chemical_list: D020413:3' Untranslated Regions; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; C555159:MIRN142 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C463963:RAB11FIP2 protein, human; D020691:rab GTP-Binding Proteins
keywords: exosome transfer; human T cells; human endothelial cells; microRNA; vascular permeability