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Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 3, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn180
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A

Karl-Otto Larsen1,2,3, Birgitte Lygren4, Ivar Sjaastad2,3,5, Kurt A. Krobert3,6, Kristin Arnkværn2,3, Geir Florholmen2,3, Ann-Kristin Ruud Larsen7, Finn Olav Levy3,6, Kjetil Taskén4, Ole Henning Skjønsberg1 and Geir Christensen2,3

1 Department of Pulmonary Medicine, Ullevål University Hospital, University of Oslo, Oslo, Norway
2 Institute for Experimental Medical Research, Ullevål University Hospital, Oslo, Norway
3 Center for Heart Failure Research, University of Oslo, Oslo, Norway
4 The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
5 Department of Cardiology, Ullevål University Hospital, Oslo, Norway
6 Department of Pharmacology, University of Oslo, Oslo, Norway
7 Department of Immunology and Transfusion Medicine, Ullevål University Hospital, Oslo, Norway

Corresponding author: Karl-Otto Larsen, MD Institute for Experimental Medical Research Surgical Building 4th floor Ullevål University Hospital Kirkeveien 166, N-0407 Oslo, Norway Fax: +4723016799 Phone: +4723016800 E-mail: karlottl{at}medisin.uio.no

Aims: 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.

Methods: In C57Bl/6j mice exposed to 10% oxygen, signaling 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 hours.

Results: The β-adrenergic pathway in the myocardium was not altered by alveolar hypoxia, as assessed by measurements of β-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 to 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 inducing an increase in PP2A and thereby a reduction in phosphorylation of phospholamban at Ser16.

Time for primary review: 17 days


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