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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aconitate Hydratase / metabolism
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Animals
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Catalase / chemistry
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Cell Survival
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Cells, Cultured
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Cytochromes c / metabolism
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Fibroblasts / metabolism
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Glutathione / metabolism
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Glutathione Disulfide / metabolism
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Glutathione Peroxidase / metabolism
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Glutathione Reductase / metabolism
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Heart Ventricles / pathology
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Heart Ventricles / physiopathology
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Hemodynamics
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Homeodomain Proteins / metabolism
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Hydrogen Peroxide / pharmacology
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Intramolecular Oxidoreductases / deficiency
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / metabolism*
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Macrophage Migration-Inhibitory Factors / deficiency
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Macrophage Migration-Inhibitory Factors / genetics
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Macrophage Migration-Inhibitory Factors / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria, Heart / metabolism
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Myocardial Reperfusion Injury / metabolism*
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Myocardial Reperfusion Injury / pathology
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Myocardium / metabolism
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Myocardium / pathology
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Oxidation-Reduction
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Oxidative Stress*
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Reactive Oxygen Species / metabolism
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Superoxide Dismutase / metabolism
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Thioredoxins / metabolism
Substances
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Homeodomain Proteins
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Macrophage Migration-Inhibitory Factors
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Prrx1 protein, mouse
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Prrx2 protein, mouse
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Reactive Oxygen Species
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Thioredoxins
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Cytochromes c
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Hydrogen Peroxide
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Catalase
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Glutathione Peroxidase
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Superoxide Dismutase
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Glutathione Reductase
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Aconitate Hydratase
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Intramolecular Oxidoreductases
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Mif protein, mouse
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Glutathione
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Glutathione Disulfide