Limiting Cardiac Ischemic Injury by Pharmacological Augmentation of Macrophage Migration Inhibitory Factor–AMP-Activated Protein Kinase Signal Transduction

Abstract

Background Macrophage migration inhibitory factor (MIF) exerts a protective effect on ischemic myocardium by activating AMP-activated protein kinase (AMPK). Small molecules that increase the affinity of MIF for its receptor have been recently designed, and we hypothesized that such agonists may enhance AMPK activation and limit ischemic tissue injury. Methods and Results Treatment of cardiomyocytes with the candidate MIF agonist, MIF20, augmented AMPK phosphorylation, increased by 50% the surface localization of glucose transporter, and enhanced by 25% cellular glucose uptake when compared to MIF alone. In mouse hearts perfused with MIF20 prior to no-flow ischemia and reperfusion, post-ischemic left ventricular function improved commensurately with an increase in cardiac MIF-AMPK activation and an augmentation in myocardial glucose uptake. By contrast, small molecule MIF agonism was not effective in cells or tissues genetically deficient in MIF or the MIF receptor, verifying the specificity of MIF20 for MIF-dependent AMPK signaling. The protective effect of MIF20 also was evident in an in vivo regional ischemia model. Mice treated with MIF20 followed by left coronary artery occlusion and reperfusion showed a significant reduction in infarcted myocardium. Conclusions These data support the pharmacologic utility of small molecule MIF agonists in enhancing AMPK activation and reducing cardiac ischemic injury.

MIFallele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis

“…expression unifies these observations with the invasive character of rheumatoid synovial fibroblasts and their enrichment for the protumorigenic CD44v3 and CD44v6 isoforms (42,43). We also confirmed a direct role for MIF in the adhesiveness of rheumatoid synovial fibroblasts, which is considered important for the formation of invasive pannus (2).…”

“…Instead, MIF binding to CD74 initiates CD44 association with CD74 to create functional signal transduction units that induce downstream MAPK phosphorylation. MIF-dependent CD74-CD44 association, as assessed by FRET and ERK1/2 phosphorylation, also was modulated by two recently developed pharmacologic agents that bind at the interface of MIF with CD74 to either increase or decrease MIF binding affinity and produce corresponding agonist or antagonist effects in vivo (41)(42)(43)60).…”

“…Notably, recombinant elimination of CD74 Ser-202 (YFP-CD74ΔCS)-which is the site of a posttranslational chondroitin sulfate modification hypothesized to facilitate CD74/CD44 membrane interactions (39)-did not influence on MIF's ability to We tested the impact on MIF-dependent FRET and signal transduction of two small-molecule pharmacologic MIF modulators: MIF098 and MIF020 (40,41). These molecules bind specifically to the MIF/CD74 interface to either reduce (e.g., MIF098) or increase (e.g., MIF020) its K D with CD74, leading to corresponding antagonist or agonist effects on signal transduction and biologic action (42,43). The addition of the MIF antagonist MIF098 and the MIF agonist MIF20 to YFP-CD74/ CD44-CFP-expressing cells modulated FRET efficiency and ERK1/2 phosphorylation in the direction predicted from the pharmacologic action of these small molecules (Fig.…”

Role of macrophage migration inhibitory factor in age-related lung disease

“…Pharmacological development in this area is advancing and has been facilitated by unique features of the MIF-CD74 interaction (126) and the recent discovery, using structure-based molecular design, of not only MIF antagonists but small molecule agonists that act to increase MIF's affinity and activation of CD74 (63). Whereas MIF antagonists may be utilized for those indications where excessive MIF production is a clinical feature, small molecule agonists may offer utility in chronic or age-related MIF deficiency (150). Ultimately, such therapies could provide precision-based medical ap- …”

4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

“…Recent findings indicated that MIF binding to CD74 stimulated heart and muscle glucose uptake, and that the autocrine/paracrine effects of endogenous cardiac MIF contributed to AMP-activated protein kinase (AMPK) activation and glucose uptake during ischemia (Wang et al 2014). Moreover, MIF can operate intracellularly in protein-protein interactions with proteins that modulate the intracellular redox state (Thiele & Bernhagen 2005) and with several key proteins that govern the cell cycle.…”