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ABSTRACT
Introduction: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia.
Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner.
Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and autoimmunity.
Article highlights
Experimental animal studies of Mif gene deletion or anti-MIF intervention establish an upstream role for MIF in the endothelial response to injury and atherosclerosis disease progression.
Commonly occurring high expression MIF alleles defined by >5 CATT repeats at the −794 MIF (CATT)5-8 promoter site or the closely associated −173*C SNP, which in linkage disequilibrium with CATT7, are associated with more advanced atherosclerosis and CVD events in different population-based cohort studies.
MIF and its homolog MIF-2 exhibit cardioprotective function in murine models of acute myocardial ischemia by signaling through the common CD74/CD44 MIF receptor complex to activate AMPK and promote energy conserving pathways.
MIF-2 lacks the MIF pseudo-(E)LR domain necessary for CXCR2 activation and is likely to be a preferential agent for therapeutic cardioprotection during acute myocardial ischemia.
The small molecule MIF agonist MIF20 enhances MIF signaling through CD74 and shows cardioprotective action in mouse models of cardiac ischemia.
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Declaration of interest
L. Young and R. Bucala are co-Inventors on patents describing the potential clinical applications of anti-MIF or MIF agonism. In addition, R. Bucala is a founder of MIFCOR, Inc., which has licensed MIF modulators from Yale University and is endeavoring to develop MIF-2 and MIF agonists for ischemic tissue protection. L. Young has received research funding from MIFCOR. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.