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Cardiovascular Research Advance Access first published online on November 18, 2008
This version [Corrected Proof] published online on December 18, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn312
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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.

Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart

Jutta Meyer-Kirchrath1,*, Melanie Martin1, Christina Schooss1, Christoph Jacoby2, Ulrich Flögel2, Andrea Marzoll1, Jens W. Fischer3, Jürgen Schrader2, Karsten Schrör1 and Thomas Hohlfeld1

1 Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum, Heinrich-Heine-Universität, Moorenstr. 5, D-40225 Düsseldorf, Germany
2 Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität, Düsseldorf, Germany
3 Institut für Pharmakologie, Universitätsklinikum Essen

* Corresponding author. Tel: +49 211 81 12500; fax: +49 211 81 14781. E-mail address: meyerj{at}uni-duesseldorf.de

Aims: Prostaglandin E2 (PGE2) has been shown to mediate anti-ischaemic effects and cardiomyocyte hypertrophy and there is evidence for an involvement of the prostaglandin EP3-receptor subtype. This study focuses on the EP3-mediated hypertrophic action and investigates intracellular signalling pathways of the EP3-receptor subtype in the murine heart.

Methods and results: Cardiac function was analyzed in vivo by magnetic resonance imaging (MRI) in transgenic (tg) mice with cardio-specific overexpression of the EP3 receptor in comparison with wild-type (wt) mice. Left ventricular (LV) function was determined in isolated perfused hearts subjected to 60 min of zero-flow ischaemia and 45 min of reperfusion. Calcineurin activity and nuclear activity of nuclear factor of activated T-cells (NFAT) were determined by a modified malachite green assay and ELISA, respectively. Extracellular matrix compounds were analyzed by RT–PCR and histology. MRI indicated a significant increase in end-diastolic and end-systolic volume in tg hearts. LV ejection fraction was severely decreased in tg hearts while the relative LV mass was significantly increased. In Langendorff perfused hearts, EP3-receptor overexpression resulted in a marked blunting of the ischaemia-induced increase in LV end-diastolic pressure and creatine kinase release. Analysis of EP3-receptor-mediated signalling revealed significantly increased calcineurin activity and nuclear activity of NFAT in tg hearts. Moreover, elevated mRNA levels of collagen types I and III as well as the collagen-binding proteoglycans biglycan and decorin were detected in tg hearts.

Conclusion: EP3-receptor-mediated signalling results in a significant anti-ischaemic action and activation of the pro-hypertrophic calcineurin signalling pathway, suggesting the involvement of the EP3 subtype in both PGE2-mediated cardioprotection as well as cardiac hypertrophy.

KEYWORDS Calcineurin; Hypertrophy; NFAT; Prostaglandins; EP3 receptor

Time for primary review: 41 days


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