Cardioprotection Through S-Nitros(yl)ation of Macrophage Migration Inhibitory Factor
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. MIF 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 which regulates the protective functional phenotype of MIF in myocardial reperfusion injury. MIF contains three cysteine (Cys) residues; using recombinant wtMIF and site-specific MIF mutants, we have identified Cys-81 to be modified by S-nitros(yl)ation, whereas the CXXC-derived Cys residues of MIF remained unaffected. The selective S-nitrosothiol (SNO) formation at Cys-81 led to a doubling of the oxidoreductase activity of MIF. Importantly, SNO-MIF formation was measured both in vitro and in vivo and led to a decrease in cardiomyocyte apoptosis in the reperfused heart. This was paralleled by a SNO-MIF- but not Cys81Ser-MIF mutant-dependent reduction of infarct size in an in vivo model of myocardial ischemia/reperfusion (I/R) 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.
- Received September 20, 2011.
- Accepted March 8, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited