1. Cardiovascular Medicine Section of the Department of Internal Medicine,
2. Rheumatology Section of the Department of Internal Medicine,
3. Department of Pathology, and,
4. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
5. Department of Medicine II, Hokkaido University, Sapporo, 060-8638, Japan
6. These authors contributed equally to this work.
7. Present address: University of Wyoming School of Pharmacy, Laramie, Wyoming 82072, USA.

Correspondence to: Lawrence H. Young^1,4,6 Correspondence and requests for materials should be addressed to L.H.Y. (Email: lawrence.young@yale.edu).

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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