Publication Date:
2008-02-01
Description:
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 apoptosis. A role for circulating hormones such as adiponectin and leptin 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 inflammation, 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 polymorphism 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Edward J -- Li, Ji -- Leng, Lin -- McDonald, Courtney -- Atsumi, Toshiya -- Bucala, Richard -- Young, Lawrence H -- England -- Nature. 2008 Jan 31;451(7178):578-82. doi: 10.1038/nature06504.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Medicine Section of the Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235500" target="_blank"〉PubMed〈/a〉
Keywords:
AMP-Activated Protein Kinases
;
Animals
;
Anoxia/enzymology/genetics/metabolism
;
Antigens, Differentiation, B-Lymphocyte/genetics/metabolism
;
Coronary Artery Disease/genetics
;
Enzyme Activation
;
Genetic Predisposition to Disease
;
Genotype
;
Glucose/metabolism
;
Histocompatibility Antigens Class II/genetics/metabolism
;
Humans
;
Macrophage Migration-Inhibitory Factors/deficiency/genetics/*metabolism/secretion
;
Mice
;
Multienzyme Complexes/*metabolism
;
Myocardial Ischemia/enzymology/genetics/*metabolism
;
Myocardial Reperfusion Injury/physiopathology/prevention & control
;
Myocardium/enzymology/metabolism
;
Polymorphism, Genetic/genetics
;
Promoter Regions, Genetic/genetics
;
Protein-Serine-Threonine Kinases/*metabolism
;
Rats
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink