title: Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction.
abstract: OBJECTIVE
  Interleukin (IL)-18 has been reported to be an important predictor for mortality in ischemic heart disease. IL-18 has proinflammatory properties, induces cell death and stimulates nitric oxide production. We hypothesized that following myocardial infarction (MI) an increased myocardial IL-18 production occurs, which may be involved in the pathogenesis of post-ischemic heart failure.
  
  
  RESULTS
  Seven days after induction of MI in the mouse, myocardial hypertrophy and pulmonary edema were observed. RNase protection assay of tissue from the non-infarcted left ventricular myocardium revealed an increase in IL-18 (2.0-fold; P<0.001) and IL-1 beta (1.6-fold; P<0.001) mRNA after MI. Enhanced abundance of pro-IL-18 (1.4-fold; P<0.05), IL-18 receptor (3.5-fold; P<0.05) and IL-18 binding proteins (1.6-fold; P<0.05) was also demonstrated, whereas cardiac IL-18 protein decreased by 25% (P<0.05) following MI. However, the concentration of circulating IL-18 was significantly elevated (MI; 90.4+/-11.7 pg/ml, sham; 47.2+/-4.2 pg/ml; P<0.001). After MI, enhanced cardiac activity of the pro-IL-18 processing enzyme, caspase-1, was measured. Additionally, a 3.4-fold increase (P<0.001) in the activity of the IL-18 degrading enzyme, caspase-3, was found in cardiac tissue, which may explain the observed reduction of cardiac IL-18 protein abundance. Finally, IL-18 reduced shortening of electrically stimulated adult cardiomyocytes and left ventricular contractility in vivo.
  
  
  CONCLUSIONS
  After MI in the mouse, increased production of cardiac IL-18 mRNA and pro-IL-18, as well as circulating IL-18 occurs. Since IL-18 also reduced myocardial contractility, we suggest that IL-18 may be involved in the pathogenesis of contractile dysfunction following MI.
authors.affiliation: Institute for Experimental Medical Research, Ullevål University Hospital, 0407 Oslo, Norway. p.r.woldbak@ioks.uio.no
authors.forename: Per Reidar
authors.initials: PR
authors.lastname: Woldbaek
authors.forename: Theis
authors.initials: T
authors.lastname: Tønnessen
authors.forename: Unni Lie
authors.initials: UL
authors.lastname: Henriksen
authors.forename: Geir
authors.initials: G
authors.lastname: Florholmen
authors.forename: Per Kristian
authors.initials: PK
authors.lastname: Lunde
authors.forename: Torstein
authors.initials: T
authors.lastname: Lyberg
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D004727:Endothelium / Q000276:immunology; D015870:Gene Expression; D006023:Glycoproteins / Q000032:analysis; D015151:Immunoblotting / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000276:immunology; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000097:blood / Q000276:immunology*; D009206:Myocardium / Q000276:immunology*; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis*; D018123:Receptors, Interleukin / Q000032:analysis
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D011498:Protein Precursors; D012333:RNA, Messenger; D018123:Receptors, Interleukin; C118370:interleukin-18 binding protein; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1