title: Differential roles of cardiac and leukocyte derived macrophage migration inhibitory factor in inflammatory responses and cardiac remodelling post myocardial infarction.
abstract: Myocardial infarction (MI) provokes regional inflammation which facilitates the healing, whereas excessive inflammation leads to adverse cardiac remodelling. Our aim was to determine the role of macrophage migration inhibitory factor (MIF) in inflammation and cardiac remodelling following MI. Wild type (WT) or global MIF deficient (MIFKO) mice were subjected to coronary artery occlusion. Compared to WT mice, MIFKO mice had a significantly lower incidence of post-MI cardiac rupture (27% vs. 53%) and amelioration of cardiac remodelling. These were associated with suppressed myocardial leukocyte infiltration, inflammatory mediators' expression, and reduced activity of MMP-2, MMP-9, p38 and JNK MAPK. Infarct myocardium-derived or exogenous MIF mediated macrophage chemotaxis in vitro that was suppressed by inhibition of p38 MAPK or NF-κB. To further dissect the role of MIF derived from different cellular sources in post-MI cardiac remodelling, we generated chimeric mice with MIF deficiency either in bone marrow derived-cells (WT(KO)) or in somatic-cells (KO(WT)). Compared to WT and KO(WT) mice, WT(KO) mice had reduced rupture risk and ameliorated cardiac remodelling, associated with attenuated regional leukocyte infiltration and expression of inflammatory mediators. In contrast, KO(WT) mice had delayed healing and enhanced expression of M1 macrophage markers, but diminished expression of M2 markers during the early healing phase. In conclusion, global MIF deletion protects the heart from post-infarct cardiac rupture and remodelling through suppression of leukocyte infiltration and inflammation. Leukocyte-derived MIF promotes inflammatory responses after MI, whereas cardiac-derived MIF affects early but not ultimate healing process.
authors: Baker IDI Heart and Diabetes Institute, Australia; Department of Cardiovascular Medicine, Alfred Hospital, Australia.
authors: David A
authors: DA
authors: White
authors: Baker IDI Heart and Diabetes Institute, Australia.
authors: Yidan
authors: Y
authors: Su
authors: Baker IDI Heart and Diabetes Institute, Australia.
authors: Peter
authors: P
authors: Kanellakis
authors: Baker IDI Heart and Diabetes Institute, Australia.
authors: Helen
authors: H
authors: Kiriazis
authors: Centre for Inflammatory Diseases, Southern Clinical School, Monash University, Australia.
authors: Eric F
authors: EF
authors: Morand
authors: Yale University School of Medicine, New Haven, CT, USA.
authors: Richard
authors: R
authors: Bucala
authors: Baker IDI Heart and Diabetes Institute, Australia; Department of Cardiovascular Medicine, Alfred Hospital, Australia; Department of Medicine, Central Clinical School, Monash University, Australia.
authors: Anthony M
authors: AM
authors: Dart
authors: Baker IDI Heart and Diabetes Institute, Australia; Department of Surgery, Central Clinical School, Monash University, Australia. Electronic address: xiaoming.gao@bakeridi.edu.au.
authors: Xiao-Ming
authors: XM
authors: Gao
authors: Baker IDI Heart and Diabetes Institute, Australia; Department of Medicine, Central Clinical School, Monash University, Australia. Electronic address: xiao-jun.du@bakeridi.edu.au.
authors: Xiao-Jun
authors: XJ
authors: Du
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006342:Heart Rupture, Post-Infarction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: Healing; Inflammation; Macrophage migration inhibitory factor; Myocardial infarction