title: Endotoxin-induced myocardial dysfunction: effects of macrophage migration inhibitory factor neutralization.
abstract: The pathophysiology of sepsis-induced myocardial dysfunction still remains controversial. Macrophage migration inhibitory factor (MIF) has recently been identified as a cardiac-derived myocardial depressant factor in septic shock. Putative mechanisms by which MIF affects cardiac function are unknown. In an investigation of possible mechanisms of action, a rat model of endotoxin toxicity was designed using intraperitoneal (I/P) injection of lipopolysaccharides (LPS) with or without coinfusion of neutralizing anti-MIF or isotypic-matched antibodies. Echocardiographic evaluation revealed that MIF neutralization reversed endotoxin-induced myocardial dysfunction at 24 hours after injection. RNase protection assay (RPA) and Western blot established that MIF neutralization prevented LPS-induced mRNA expression and production of heart-derived inflammatory paracrine and autocrine cytokines such as IL-1s and IL-6. Moreover, MIF immunoneutralization increased heart Bcl-2/Bax protein ratio and suppressed endotoxin-induced release of mitochondrial cytochrome-c, as demonstrated by Western blotting. Inhibition of mitochondrial loss of cytochrome-c decreased in heart caspase-3 activity at 6 and 24 hours after injection. MIF neutralization also restored the LPS-induced deficient nuclear translocation of phospho-Akt and consequently the expression of the heart survival nuclear factor GATA-4. The restoration of the translocation/expression of survival factors by MIF inhibition resulted in lowered endotoxin-induced DNA fragmentation at 24 hours, a hallmark of downstream cardiomyocyte apoptosis. Our data indicate that early inactivation of MIF significantly reverses the imbalance of proapoptotic to prosurvival pathways and reduces acute inflammation of the heart thereby improving myocardial dysfunction induced by endotoxin.
authors.affiliation: Groupe de Recherche en Physiopathologie Respiratoire, Centre de Recherche Clinique, Universite de Sherbrooke, PQ, Canada.
authors.forename: Frederic
authors.initials: F
authors.lastname: Chagnon
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Olivier
authors.initials: O
authors.lastname: Lesur
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D050991:GATA4 Transcription Factor; D006331:Heart Diseases / Q000209:etiology*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D008297:Male; D008928:Mitochondria / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000150:complications*; D012772:Shock, Septic / Q000209:etiology; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D004731:Endotoxins; D050991:GATA4 Transcription Factor; D007375:Interleukin-1; D015850:Interleukin-6; D008263:Macrophage Migration-Inhibitory Factors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt