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Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart

Abstract

Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis1. A role for circulating hormones such as adiponectin2 and leptin3 in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation4, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism5 have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.

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Figure 1: Role of MIF in heart muscle AMPK signalling during hypoxia.
Figure 2: Heart MIF expression and release triggered by ischaemia.
Figure 3: Genetic MIF deletion impairs ischaemic heart AMPK activation and glucose uptake, and exacerbates post-ischaemic cardiac dysfunction and injury.
Figure 4: Human MIF promoter genotype determines MIF secretion and AMPK activation during hypoxia.

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Acknowledgements

This work was supported by the US Public Health Service. The authors wish to thank K. Kevill and J. Hu for technical assistance, and G. Holman, S. Cushman and A. Edelman for providing reagents.

Author Contributions E.J.M. and J.L. each contributed to the experimental work, project planning, data analysis and writing of the manuscript. L.L. contributed to the experimental work and project planning. C.M. contributed to reagent development, validation and preparation. T.A. made the initial observation of MIF induction of AMPK phosphorylation. L.H.Y. and R.B. contributed to the project planning, data analysis and writing of the manuscript. L.H.Y. and R.B. were co-contributing senior authors.

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Correspondence to Lawrence H. Young.

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Yale University has applied for a patent describing the therapeutic use of MIF agonism and AMPK activation. R.B. is an inventor on a patent for MIF genotyping.

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The file contains Supplementary Figures 1-5 with Legends and additional references. (PDF 1866 kb)

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Miller, E., Li, J., Leng, L. et al. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451, 578–582 (2008). https://doi.org/10.1038/nature06504

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