1. Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart
- Author
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Jutta Meyer-Kirchrath, Thomas Hohlfeld, Christina Schooss, Jürgen Schrader, Ulrich Flögel, Jens W. Fischer, Andrea Marzoll, Karsten Schrör, Melanie Martin, and Christoph Jacoby
- Subjects
medicine.medical_specialty ,Physiology ,Decorin ,Prostaglandin ,Cardiomegaly ,GTP-Binding Protein alpha Subunits, Gi-Go ,Ventricular Function, Left ,Muscle hypertrophy ,Mice ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,Cyclic AMP ,medicine ,Animals ,Receptors, Prostaglandin E ,Myocytes, Cardiac ,Transgenes ,Prostaglandin E2 ,Ventricular Remodeling ,biology ,Calcineurin ,Biglycan ,NFAT ,Magnetic Resonance Imaging ,Endocrinology ,chemistry ,Receptors, Prostaglandin E, EP3 Subtype ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Creatine kinase ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,medicine.drug - Abstract
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.
- Published
- 2008