title: IL-18 neutralization during alveolar hypoxia improves left ventricular diastolic function in mice.
abstract: OBJECTIVE
  In patients, an association exists between pulmonary diseases and diastolic dysfunction of the left ventricle (LV). We have previously shown that alveolar hypoxia in mice induces LV diastolic dysfunction and that mice exposed to hypoxia have increased levels of circulating interleukin-18 (IL-18), suggesting involvement of IL-18 in development of diastolic dysfunction. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. In this study, we hypothesized that neutralization of IL-18 during alveolar hypoxia would improve LV diastolic function.
  
  
  METHODS
  Mice were exposed to 10% oxygen for 2 weeks while treated with IL-18BP or vehicle. Cardiac function and morphology were measured using echocardiography, intraventricular pressure measurements and magnetic resonance imaging (MRI). For characterization of molecular changes in the heart, both real-time PCR and Western blotting were performed. ELISA technique was used to measure levels of circulating cytokines.
  
  
  RESULTS
  As expected, exposure to hypoxia-induced LV diastolic dysfunction, as shown by prolonged time constant of isovolumic relaxation (τ). Improved relaxation with IL-18BP treatment was demonstrated by a significant reduction towards control τ values. Decreased levels of phosphorylated phospholamban (P-PLB) in hypoxia, but normalization by IL-18BP treatment suggest a role for IL-18 in regulation of calcium-handling proteins in hypoxia-induced diastolic dysfunction. In addition, MRI showed less increase in right ventricular (RV) wall thickness in IL-18BP-treated animals exposed to hypoxia, indicating an effect on RV hypertrophy.
  
  
  CONCLUSIONS
  Neutralization of IL-18 during alveolar hypoxia improves LV diastolic function and partly prevents RV hypertrophy.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: V
authors.initials: V
authors.lastname: Hillestad
authors.forename: E K S
authors.initials: EK
authors.lastname: Espe
authors.forename: F
authors.initials: F
authors.lastname: Cero
authors.forename: K O
authors.initials: KO
authors.lastname: Larsen
authors.forename: I
authors.initials: I
authors.lastname: Sjaastad
authors.forename: S
authors.initials: S
authors.lastname: Nygård
authors.forename: O H
authors.initials: OH
authors.lastname: Skjønsberg
authors.forename: G
authors.initials: G
authors.lastname: Christensen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D020382:Interleukin-18 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein
keywords: diastolic dysfunction; hypoxia; interleukin-18; pulmonary hypertension; right ventricular hypertrophy