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

AbstractBACKGROUND:
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.
AuthorsPeter 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
JournalCirculation (Circulation) Vol. 125 Issue 15 Pg. 1880-9 (Apr 17 2012) ISSN: 1524-4539 [Electronic] United States
PMID22415145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Macrophage Migration-Inhibitory Factors
  • Nitric Oxide
  • Cysteine
Topics
  • Animals
  • Cysteine (metabolism)
  • Cytoprotection
  • Humans
  • Macrophage Migration-Inhibitory Factors (metabolism)
  • Mice
  • Myocardial Reperfusion Injury (etiology, prevention & control)
  • Nitric Oxide (metabolism)

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