title: Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A.
abstract: OBJECTIVE
  Chronic obstructive pulmonary disease with alveolar hypoxia is associated with diastolic dysfunction in the right and left ventricle (LV). LV diastolic dysfunction is not caused by increased afterload, and we recently showed that reduced phosphorylation of phospholamban at serine (Ser) 16 may explain the reduced relaxation of the myocardium. Here, we study the mechanisms leading to the hypoxia-induced reduction in phosphorylation of phospholamban at Ser16.
  
  
  RESULTS
  In C57Bl/6j mice exposed to 10% oxygen, signalling molecules were measured in cardiac tissue, sarcoplasmic reticulum (SR)-enriched membrane preparations, and serum. Cardiomyocytes isolated from neonatal mice were exposed to interleukin (IL)-18 for 24 h. The beta-adrenergic pathway in the myocardium was not altered by alveolar hypoxia, as assessed by measurements of beta-adrenergic receptor levels, adenylyl cyclase activity, and subunits of cyclic AMP-dependent protein kinase. However, alveolar hypoxia led to a significantly higher amount (124%) and activity (234%) of protein phosphatase (PP) 2A in SR-enriched membrane preparations from LV compared with control. Serum levels of an array of cytokines were assayed, and a pronounced increase in IL-18 was observed. In isolated cardiomyocytes, treatment with IL-18 increased the amount and activity of PP2A, and reduced phosphorylation of phospholamban at Ser16 to 54% of control.
  
  
  CONCLUSIONS
  Our results indicate that the diastolic dysfunction observed in alveolar hypoxia might be caused by increased circulating IL-18, thereby inducing an increase in PP2A and a reduction in phosphorylation of phospholamban at Ser16.
authors.affiliation: Department of Pulmonary Medicine, Ullevål University Hospital, University of Oslo, Oslo, Norway. karlottl@medisin.uio.no
authors.forename: Karl-Otto
authors.initials: KO
authors.lastname: Larsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Lygren
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Krobert
authors.forename: Kristin
authors.initials: K
authors.lastname: Arnkvaern
authors.forename: Geir
authors.initials: G
authors.lastname: Florholmen
authors.forename: Ann-Kristin Ruud
authors.initials: AK
authors.lastname: Larsen
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.forename: Ole Henning
authors.initials: OH
authors.lastname: Skjønsberg
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D054144:Heart Failure, Diastolic / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020382:Interleukin-18 / Q000097:blood*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009929:Organ Size; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000262:Adenylyl Cyclases; D002118:Calcium; D002135:Calcium-Binding Proteins; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines; D020382:Interleukin-18; D054648:Protein Phosphatase 2; D051057:Proto-Oncogene Proteins c-akt; D011943:Receptors, Adrenergic, beta; D000099211:Phospholamban