title: The mitochondria-targeted anti-oxidant MitoQ decreases ischemia-reperfusion injury in a murine syngeneic heart transplant model.
abstract: BACKGROUND
  Free radical production and mitochondrial dysfunction during cardiac graft reperfusion is a major factor in post-transplant ischemia-reperfusion (IR) injury, an important underlying cause of primary graft dysfunction. We therefore assessed the efficacy of the mitochondria-targeted anti-oxidant MitoQ in reducing IR injury in a murine heterotopic cardiac transplant model.
  
  
  METHODS
  Hearts from C57BL/6 donor mice were flushed with storage solution alone, solution containing the anti-oxidant MitoQ, or solution containing the non-anti-oxidant decyltriphenylphosphonium control and exposed to short (30 minutes) or prolonged (4 hour) cold preservation before transplantation. Grafts were transplanted into C57BL/6 recipients and analyzed for mitochondrial reactive oxygen species production, oxidative damage, serum troponin, beating score, and inflammatory markers 120 minutes or 24 hours post-transplant.
  
  
  RESULTS
  MitoQ was taken up by the heart during cold storage. Prolonged cold preservation of donor hearts before IR increased IR injury (troponin I, beating score) and mitochondrial reactive oxygen species, mitochondrial DNA damage, protein carbonyls, and pro-inflammatory cytokine release 24 hours after transplant. Administration of MitoQ to the donor heart in the storage solution protected against this IR injury by blocking graft oxidative damage and dampening the early pro-inflammatory response in the recipient.
  
  
  CONCLUSIONS
  IR after heart transplantation results in mitochondrial oxidative damage that is potentiated by cold ischemia. Supplementing donor graft perfusion with the anti-oxidant MitoQ before transplantation should be studied further to reduce IR-related free radical production, the innate immune response to IR injury, and subsequent donor cardiac injury.
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Dare
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Prime
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rogatti
authors.affiliation: Papworth Hospital National Health Service Foundation Trust, Papworth Everard, Cambridge, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Goddard
authors.affiliation: Department of Surgery, University of Cambridge, and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Bolton
authors.affiliation: Department of Surgery, University of Cambridge, and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.affiliation: Department of Surgery, University of Cambridge, and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Pettigrew
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, University of Cambridge and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom. Electronic address: mpm@mrc-mbu.cam.ac.uk.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Surgery, University of Cambridge, and the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Saeb-Parsy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism; D016027:Heart Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018977:Micronutrients / Q000627:therapeutic use; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D009926:Organ Preservation; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D018384:Oxidative Stress; D055031:Primary Graft Dysfunction / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D018977:Micronutrients; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C429014:mitoquinone
keywords: MitoQ; ischemia; mitochondria-targeted anti-oxidants; reperfusion; transplantation