Cardioprotection Through S-nitros(yl)ation of Macrophage Migration Inhibitory Factor

Circulation. 2012 Apr 17;125(15):1880-9. doi: 10.1161/CIRCULATIONAHA.111.069104. Epub 2012 Mar 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cysteine / metabolism
  • Cytoprotection
  • Humans
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Mice
  • Myocardial Reperfusion Injury / etiology
  • Myocardial Reperfusion Injury / prevention & control*
  • Nitric Oxide / metabolism

Substances

  • Macrophage Migration-Inhibitory Factors
  • Nitric Oxide
  • Cysteine