Limiting Cardiac Ischemic Injury by Pharmacologic Augmentation of MIF-AMPK Signal Transduction
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.
- Received December 24, 2012.
- Revision received May 27, 2013.
- Accepted June 3, 2013.