Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart.
OBJECTIVE
Prostaglandin E(2) (PGE(2)) has been shown to mediate anti-ischaemic effects and cardiomyocyte hypertrophy and there is evidence for an involvement of the prostaglandin EP(3)-receptor subtype. This study focuses on the EP(3)-mediated hypertrophic action and investigates intracellular signalling pathways of the EP(3)-receptor subtype in the murine heart.


RESULTS
Cardiac function was analyzed in vivo by magnetic resonance imaging (MRI) in transgenic (tg) mice with cardio-specific overexpression of the EP(3) 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, EP(3)-receptor overexpression resulted in a marked blunting of the ischaemia-induced increase in LV end-diastolic pressure and creatine kinase release. Analysis of EP(3)-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.


CONCLUSIONS
EP(3)-receptor-mediated signalling results in a significant anti-ischaemic action and activation of the pro-hypertrophic calcineurin signalling pathway, suggesting the involvement of the EP(3) subtype in both PGE(2)-mediated cardioprotection as well as cardiac hypertrophy.
Meyer-Kirchrath
Jutta
J
Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum, Heinrich-Heine-Universität, Moorenstr. 5, D-40225 Düsseldorf, Germany. meyerj@uni-duesseldorf.de
Martin
Melanie
M
Schooss
Christina
C
Jacoby
Christoph
C
Flögel
Ulrich
U
Marzoll
Andrea
A
Fischer
Jens W
JW
Schrader
Jürgen
J
Schrör
Karsten
K
Hohlfeld
Thomas
T
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D006332:Cardiomegaly / Q000209:etiology*; D000242:Cyclic AMP / Q000096:biosynthesis; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D008279:Magnetic Resonance Imaging; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015398:Signal Transduction; D019076:Transgenes; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D000242:Cyclic AMP; D019703:Calcineurin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go