title: Exogenous Administration of Recombinant MIF at Physiological Concentrations Failed to Attenuate Infarct Size in a Langendorff Perfused Isolated Mouse Heart Model.
abstract: OBJECTIVE
  Evidence suggests a two-pronged role of endogenous macrophage migration inhibitory factor (MIF) release in ischemia/reperfusion injury. We aimed to assess whether its exogenous administration confers cardioprotection.
  
  
  METHODS
  Male C57/BL6 mice were randomly allocated to receive recombinant mouse MIF (rMIF) at physiological (ng/mL) concentrations in a dose-response fashion before or after a protocol of 35 min of ischemia and 2 h of reperfusion in an isolated Langendorff-perfused model with infarct size as endpoint. Isolated primary cardiomyocytes were also used for cell survival studies using rMIF at a supra-physiological concentration of 1 μg/mL. Pro-survival kinase activation was also studied using Western blot analyses.
  
  
  RESULTS
  Exogenous MIF did not elicit a cardioprotective effect either when administered before the ischemic insult or when applied at reperfusion. rMIF did not confer protection when it was applied immediately before or after a hypoxia/reoxygenation insult in primary isolated cardiomyocytes. Consistently, hearts treated with MIF did not show a significant increase in phosphorylated Akt and ERK1/2.
  
  
  CONCLUSIONS
  The exogenous administration of rMIF in a physiological concentration range both before ischemia and at reperfusion did not show cardioprotective effects. Although these results do not address the role of endogenous MIF after an ischemic insult followed by reperfusion, they may limit the potential translational value of rMIF.
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX 2, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Rossello
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX 2, UK.
authors.forename: Niall
authors.initials: N
authors.lastname: Burke
authors.affiliation: Department of Intensive Care Medicine, University Hospital, Aachen, RWTH, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Stoppe
authors.affiliation: Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, 81377, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Bernhagen
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX 2, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX 2, UK. d.yellon@ucl.ac.uk.|NIHR UCLH Biomedical Research Centre, University College London Hospital & Medical School, London, UK. d.yellon@ucl.ac.uk.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases / Q000494:pharmacology / Q000627:therapeutic use*; D019157:Ischemic Preconditioning, Myocardial; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D010477:Perfusion; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: Ischemia–reperfusion; Ischemic preconditioning; Macrophage migration inhibitory factor; Myocardial infarction