Cardioprotection through S-nitros(yl)ation of macrophage migration inhibitory factor

Peter Luedike, Ulrike B. Hendgen-Cotta, Julia Sobierajski, Matthias Totzeck, Marcel Reeh, Manfred Dewor, Hongqi Lue, Christoph Krisp, Dirk Wolters, Malte Kelm, Jürgen Bernhagen*, Tienush Rassaf

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)

Abstract

BACKGROUND-: Macrophage migration inhibitory factor (MIF) is a structurally unique inflammatory cytokine that controls cellular signaling in human physiology and disease through extra-and intracellular processes. Macrophage migration inhibitory factor has been shown to mediate both disease-exacerbating and beneficial effects, but the underlying mechanism(s) controlling these diverse functions are poorly understood. METHODS AND RESULTS-: Here, we have identified an S-nitros(yl)ation modification of MIF that regulates the protective functional phenotype of MIF in myocardial reperfusion injury. Macrophage migration inhibitory factor contains 3 cysteine (Cys) residues; using recombinant wtMIF and site-specific MIF mutants, we have identified that Cys-81 is modified by S-nitros(yl)ation whereas the CXXC-derived Cys residues of MIF remained unaffected. The selective S-nitrosothiol formation at Cys-81 led to a doubling of the oxidoreductase activity of MIF. Importantly, S-nitrosothiol-MIF formation was measured both in vitro and in vivo and led to a decrease in cardiomyocyte apoptosis in the reperfused heart. This decrease was paralleled by a S-nitrosothiol-MIF-but not Cys81 serine (Ser)-MIF mutant-dependent reduction of infarct size in an in vivo model of myocardial ischemia/reperfusion injury. CONCLUSIONS-: S-nitros(yl)ation of MIF is a pivotal novel regulatory mechanism, providing enhanced activity resulting in increased cytoprotection in myocardial reperfusion injury.

Original languageEnglish
Pages (from-to)1880-1889
Number of pages10
JournalCirculation
Volume125
Issue number15
DOIs
Publication statusPublished - 17 Apr 2012
Externally publishedYes

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