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Targeted intracellular accumulation of macrophage migration inhibitory factor in the reperfused heart mediates cardioprotectionFinancial support: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants Be1977/4–2 (TP1 of DFG-FOR809) and GRK1508/1 (project P13) to J.B., Ra969/6–1 to T.R. and J.B. T.R. is a Heisenberg professor funded by the DFG (Ra969/7–2). PL is funded by the Medical Faculty of the University of Düsseldorf. There are no relationships with industry.
27 May 2015
Accepted after minor revision: 09 July 2015
22 November 2017 (online)
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/reoxyge-nation (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 intra-cellular accumulation of MIF by S-nitrosation may offer a novel therapeutic approach in the treatment of myocardial I/R-injury.
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