title: Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice.
abstract: Although increased levels of circulating interleukin (IL)-18 have been demonstrated in patients with cardiovascular diseases, the functional consequences of chronically increased circulating IL-18 with respect to myocardial function have not been defined. Thus we aimed to examine the effects of chronic IL-18 exposure on left ventricular (LV) function in healthy mice. Moreover, to clarify whether IL-18 has direct effects on the cardiomyocyte, we examined effects of IL-18 on cardiomyocytes in vitro. After 7 days of daily intraperitoneal injections of 0.5 microg IL-18 in healthy mice, a 40% (P < 0.05) reduction in the LV maximal positive derivative, a 25% (P < 0.05) reduction in the LV maximal rate of pressure decay, and a 2.8-fold (P < 0.001) increase in the LV end-diastolic pressure were measured, consistent with myocardial dysfunction. Furthermore, we measured a 75% (P < 0.05) reduction in beta-adrenergic responsiveness to isoproterenol. IL-18 induced myocardial hypertrophy, and there was a 2.9-fold increase (P < 0.05) in atrial natriuretic peptide mRNA expression in the LV myocardium. In vitro examinations of isolated adult rat cardiomyocytes being stimulated with IL-18 (0.1 microg/ml) exhibited an increase in peak Ca2+ transients (P < 0.05) and in diastolic Ca2+ concentrations (P < 0.05). In conclusion, this study shows that daily administration of IL-18 in healthy mice causes LV myocardial dysfunction and blunted beta-adrenergic responsiveness to isoproterenol. A direct effect of IL-18 on the cardiomyocyte in vitro was demonstrated, suggesting that IL-18 reduces the responsiveness of the myofilaments to Ca2+. Finally, induction of myocardial hypertrophy by IL-18 indicates a role for this cytokine in myocardial remodeling.
authors.affiliation: Institute for Experimental Medical Research, Ullevål University Hospital, 0407 Oslo, Norway. pewo@uus.no
authors.forename: Per Reidar
authors.initials: PR
authors.lastname: Woldbaek
authors.forename: Jørn Bodvar
authors.initials: JB
authors.lastname: Sande
authors.forename: Taevje Andreas
authors.initials: TA
authors.lastname: Strømme
authors.forename: Per Kristian
authors.initials: PK
authors.lastname: Lunde
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Torstein
authors.initials: T
authors.lastname: Lyberg
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Theis
authors.initials: T
authors.lastname: Tønnessen
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004334:Drug Administration Schedule; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000008:administration & dosage* / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D009320:Atrial Natriuretic Factor; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D018799:Intercellular Adhesion Molecule-1; D020382:Interleukin-18; D007545:Isoproterenol; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014409:Tumor Necrosis Factor-alpha; D000099211:Phospholamban