title: Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress.
abstract: Macrophage migration inhibitory factor (MIF) is a multifunctional protein that exhibits an intrinsic thiol protein oxidoreductase activity and proinflammatory activities. In the present study to examine intracellular MIF redox function, exposure of MIF-deficient cardiac fibroblasts to oxidizing conditions resulted in a 2.3-fold increase (p < 0.001) in intracellular ROS that could be significantly reduced by adenoviral-mediated reexpression of recombinant MIF. In an animal model of myocardial injury by ischemia/reperfusion (I/R), MIF-deficient hearts exhibited higher levels of oxidative stress than did wild-type hearts, as measured by significantly higher oxidized glutathione levels (decreased GSH/GSSG ratio), increased protein oxidation, reduced aconitase activity, and increased mitochondrial injury (increased cytochrome c release). The increased myocardial oxidative stress after I/R was reflected by larger infarct size (INF) in MIF-deficient hearts versus wild-type (WT) hearts (21 ± 6% vs. 8 ± 3% INF/LV; p < 0.05). In vivo hemodynamic measurements showed that left ventricular (LV) contractile function of MIF-deficient hearts subjected to 15-min ischemia failed to recover during reperfusion compared with WT hearts (LV developed pressure and ± dP/dt; p = 0.02). These data represent the first in vivo evidence in support of a cardioprotective role of MIF in the postischemic heart by reducing oxidative stress.
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, USA.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Koga
authors.forename: Agnes
authors.initials: A
authors.lastname: Kenessey
authors.forename: Saul R
authors.initials: SR
authors.lastname: Powell
authors.forename: Cristina P
authors.initials: CP
authors.lastname: Sison
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
authors.forename: Kaie
authors.initials: K
authors.lastname: Ojamaa
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000737:chemistry; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D018398:Homeodomain Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D008263:Macrophage Migration-Inhibitory Factors; C489936:Prrx1 protein, mouse; C115469:Prrx2 protein, mouse; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D000154:Aconitate Hydratase; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D005978:Glutathione; D019803:Glutathione Disulfide