title: Deletion of macrophage migration inhibitory factor protects the heart from severe ischemia-reperfusion injury: a predominant role of anti-inflammation.
abstract: Inflammation plays an important role in mediating and exacerbating myocardial ischemia-reperfusion (I/R) injury. Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, facilitates inflammation and modulates metabolism. However, the role of MIF in mediating local inflammation subsequent to ischemic myocardial injury has not been established. We hypothesized that genetic deletion of MIF protects the heart against severe I/R injury by suppressing inflammation and/or modulating energy metabolism. We showed in the mouse I/R model that duration of both ischemia and reperfusion is a determinant for the degree of regional inflammation and tissue damage. Following a prolonged cardiac I/R (60 min/24h) MIF KO mice had a significant reduction in both infarct size (26±3% vs. 45±4%, P<0.05) and cardiomyocyte apoptosis (1.4±0.2% vs. 5.4±0.4%, P<0.05) and preserved contractile function compared with WT. MIF KO mice with I/R had reduced expression of various inflammatory cytokines and mediators (P<0.05), suppressed infiltration of neutrophils (-40%) and macrophages (-33%, both P<0.05), and increased macrophage apoptosis (14.4±1.4% vs. 5.2±0.6%, P<0.05). Expression of toll-like receptor-4 (TLR-4), phosphorylation of c-Jun N-terminal kinase (JNK), and nuclear fraction of NF-κB p65 were also significantly lower in MIF KO hearts with I/R. Further, MIF KO mice exhibited a lower glucose uptake but higher fatty acid oxidation rate than that in WT (both P<0.05). In conclusion, MIF deficiency protected the heart from prolonged/severe I/R injury by suppressing inflammatory responses. We have identified a critical role of MIF in mediating severe I/R injury. Thus, MIF inhibitory therapy may be a novel strategy to protect the heart against severe I/R injury.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia. xiaoming.gao@bakeridi.edu.au
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: White
authors.forename: Yidan
authors.initials: Y
authors.lastname: Su
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Qi
authors.initials: Q
authors.lastname: Xu
authors.forename: Nicole
authors.initials: N
authors.lastname: Jennings
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Kingwell
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dart
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006439:Hemodynamics / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency* / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D051193:Toll-Like Receptors