title: Cardioprotection through S-nitros(yl)ation of macrophage migration inhibitory factor.
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.
  
  
  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.
authors.affiliation: University Hospital Düsseldorf, Medical Faculty, Division of Cardiology, Pulmonology, and Vascular Medicine, Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Luedike
authors.forename: Ulrike B
authors.initials: UB
authors.lastname: Hendgen-Cotta
authors.forename: Julia
authors.initials: J
authors.lastname: Sobierajski
authors.forename: Matthias
authors.initials: M
authors.lastname: Totzeck
authors.forename: Marcel
authors.initials: M
authors.lastname: Reeh
authors.forename: Manfred
authors.initials: M
authors.lastname: Dewor
authors.forename: Hongqi
authors.initials: H
authors.lastname: Lue
authors.forename: Christoph
authors.initials: C
authors.lastname: Krisp
authors.forename: Dirk
authors.initials: D
authors.lastname: Wolters
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Tienush
authors.initials: T
authors.lastname: Rassaf
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D019610:Cytoprotection; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D009569:Nitric Oxide; D003545:Cysteine