Targeted intracellular accumulation of macrophage migration inhibitory factor in the reperfused heart mediates cardioprotection

Julia Pohl; Ulrike R. Hendgen-Cotta; Christos Rammos; Peter Luedike; Elena Mull; Christian Stoppe; Karen Jülicher; Hongqi Lue; Marc Merx; Malte Kelm; Jürgen Bernhagen; Tienush Rassaf

doi:10.1160/TH15-05-0436

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(01): 200-212
DOI: 10.1160/TH15-05-0436

Atherosclerosis and Ischaemic Disease

Schattauer GmbH Schattauer

Targeted intracellular accumulation of macrophage migration inhibitory factor in the reperfused heart mediates cardioprotection

Julia Pohl

¹University Hospital Essen, Department of Cardiology, West-German Heart and Vascular Center Essen, Essen, Germany

,

Ulrike R. Hendgen-Cotta

¹University Hospital Essen, Department of Cardiology, West-German Heart and Vascular Center Essen, Essen, Germany

,

Christos Rammos

¹University Hospital Essen, Department of Cardiology, West-German Heart and Vascular Center Essen, Essen, Germany

,

Peter Luedike

¹University Hospital Essen, Department of Cardiology, West-German Heart and Vascular Center Essen, Essen, Germany

,

Elena Mull

¹University Hospital Essen, Department of Cardiology, West-German Heart and Vascular Center Essen, Essen, Germany

,

Christian Stoppe

²RWTH Aachen University, Institute of Biochemistry and Molecular Cell Biology, Aachen, Germany

,

Karen Jülicher

²RWTH Aachen University, Institute of Biochemistry and Molecular Cell Biology, Aachen, Germany

,

Hongqi Lue

²RWTH Aachen University, Institute of Biochemistry and Molecular Cell Biology, Aachen, Germany

,

Marc Merx

³Klinikum Region Hannover, Department of Cardiology, Vascular Medicine and Critical Care Medicine, Gehrden, Germany

⁴University Hospital Düsseldorf, Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, Düsseldorf, Germany

,

Malte Kelm

⁴University Hospital Düsseldorf, Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, Düsseldorf, Germany

,

Jürgen Bernhagen

²RWTH Aachen University, Institute of Biochemistry and Molecular Cell Biology, Aachen, Germany

,

Tienush Rassaf

¹University Hospital Essen, Department of Cardiology, West-German Heart and Vascular Center Essen, Essen, Germany

› Author Affiliations

Abstract

Summary

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.

Keywords

Cardioprotection - macrophage migration inhibitory factor - myocardial ischaemia/reperfusion injury - oxidative stress

Full Text

References

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