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

Overview

Journal Circulation

Specialty Cardiology & Vascular Diseases

Date 2013 Jun 12

PMID 23753877

Citations 43

Authors

Jingying Wang

Chao Tong

Xiaoyan Yan

Eddie Yeung

Sunilkumar Gandavadi

Alissa A Hare

Xin Du

Yibang Chen

Huabao Xiong

Changxing Ma

Lin Leng

Lawrence H Young

William L Jorgensen

Ji Li

Richard Bucala

Affiliations

Soon will be listed here.

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 in comparison with MIF alone. In mouse hearts perfused with MIF20 before no-flow ischemia and reperfusion, postischemic 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 pharmacological utility of small-molecule MIF agonists in enhancing AMPK activation and reducing cardiac ischemic injury.

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