Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A.
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.
Larsen
Karl-Otto
KO
Department of Pulmonary Medicine, Ullevål University Hospital, University of Oslo, Oslo, Norway. karlottl@medisin.uio.no
Lygren
Birgitte
B
Sjaastad
Ivar
I
Krobert
Kurt A
KA
Arnkvaern
Kristin
K
Florholmen
Geir
G
Larsen
Ann-Kristin Ruud
AK
Levy
Finn Olav
FO
Taskén
Kjetil
K
Skjønsberg
Ole Henning
OH
Christensen
Geir
G
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
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