title: Targeted intracellular accumulation of macrophage migration inhibitory factor in the reperfused heart mediates cardioprotection.
abstract: S-nitrosation of macrophage migration inhibitory factor (MIF) has been shown to be cytoprotective in myocardial ischaemia/reperfusion (I/R) injury. Since the exact mechanism of action is unknown, we here characterise the cardioprotective effects of targeted intracellular accumulation of MIF in myocardial I/R injury. We used different in vivo, ex vivo and in vitro models of myocardial I/R and hypoxia/reoxygenation (H/R) injury to determine MIF levels by immunoblots and ELISA in different phases of reperfusion and reoxygenation, respectively. We discovered a rapid decrease of cardiac MIF that was specific to the early phase of reperfusion. Posttranslational modification of MIF via S-nitrosation--proofed by a modified version of the Biotin Switch Assay--prevented this rapid decrease, leading to a targeted intracellular accumulation of MIF in the early phase of reperfusion. Intracellular MIF accumulation preserved the intracellular ability of MIF to reduce oxidative stress as shown by hydrogen peroxide and aconitase activity measurements. Infarct size measurements by TTC staining showed an overall enhanced cardioprotective effect of this protein by reduction of reperfusion injury. In summary, we have unravelled a novel mechanism of MIF-mediated cardioprotection. Targeted intracellular accumulation of MIF by S-nitrosation may offer a novel therapeutic approach in the treatment of myocardial I/R-injury.
authors: Julia
authors: J
authors: Pohl
authors: Ulrike B
authors: UB
authors: Hendgen-Cotta
authors: Christos
authors: C
authors: Rammos
authors: Peter
authors: P
authors: Luedike
authors: Elena
authors: E
authors: Mull
authors: Christian
authors: C
authors: Stoppe
authors: Karen
authors: K
authors: Jülicher
authors: Hongqi
authors: H
authors: Lue
authors: Marc W
authors: MW
authors: Merx
authors: Malte
authors: M
authors: Kelm
authors: Jürgen
authors: J
authors: Bernhagen
authors: Prof. Dr. Tienush Rassaf, West-German Heart and Vascular Center Essen, Department of Cardiology, University Hospital Essen, Hufelandstr. 55, D-45147 Essen, Germany, Tel.: +49 201 723 4801, Fax: +49 201 723 5401, E-mail: Tienush.Rassaf@uk-essen.de.
authors: Tienush
authors: T
authors: Rassaf
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006861:Hydrogen Peroxide / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D015538:Nitrosation; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D013997:Time Factors
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D006861:Hydrogen Peroxide; D000154:Aconitate Hydratase; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: Cardioprotection; macrophage migration inhibitory factor; myocardial ischaemia/reperfusion injury; oxidative stress