title: Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction.
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.
  
  
  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.
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, NY 14214-3000, USA.
authors.forename: Jingying
authors.initials: J
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Tong
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yan
authors.forename: Eddie
authors.initials: E
authors.lastname: Yeung
authors.forename: Sunilkumar
authors.initials: S
authors.lastname: Gandavadi
authors.forename: Alissa A
authors.initials: AA
authors.lastname: Hare
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Yibang
authors.initials: Y
authors.lastname: Chen
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.forename: Changxing
authors.initials: C
authors.lastname: Ma
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D005947:Glucose / Q000493:pharmacokinetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000944:Antigens, Differentiation, B-Lymphocyte; D002316:Cardiotonic Agents; D000949:Histocompatibility Antigens Class II; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; C045084:invariant chain; D055372:AMP-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D005947:Glucose
keywords: glucose transporter; ischemia; migration inhibitory factor agonist