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(Circulation. 2005;112:400-406.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Cardiospecific Overexpression of the Prostaglandin EP₃ Receptor Attenuates Ischemia-Induced Myocardial Injury

Melanie Martin, BSc^*; Jutta Meyer-Kirchrath, PhD^*; Gernot Kaber, BSc; Christoph Jacoby, PhD; Ulrich Flögel, PhD; Jürgen Schrader, MD; Ulrich Rüther, PhD; Karsten Schrör, MD; Thomas Hohlfeld, MD

From the Institut für Pharmakologie und Klinische Pharmakologie (M.M., J.M.-K., G.K., K.S., T.H.), Institut für Herz- und Kreislaufphysiologie (C.J., U.F., J.S.), and Institut für Entwicklungs- und Molekularbiologie (U.R.), Heinrich-Heine-Universität, Düsseldorf, Germany.

Correspondence to Dr Thomas Hohlfeld, Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum, Heinrich-Heine-Universität, Moorenstr 5, D-40225 Düsseldorf, Germany. E-mail hohlfeld{at}uni-duesseldorf.de

Received September 22, 2004; revision received March 17, 2005; accepted March 30, 2005.

Background— The generation of prostaglandin E₂ (PGE₂) is significantly increased in acute myocardial ischemia and reperfusion. PGE₂, in addition to other prostaglandins, protects the reperfused ischemic myocardium. It has been hypothesized that this cardioprotection is mediated by E-type prostaglandin receptors of the G_i-coupled EP₃ subtype.

Methods and Results— We tested this hypothesis by generating transgenic (tg) mice with cardiospecific overexpression of the EP₃ receptor. According to ligand binding, a 40-fold overexpression of the EP₃ receptor was achieved in membranes prepared from tg hearts compared with wild-type (wt) littermates. In isolated cardiomyocytes from tg mice, the forskolin-induced rise in cAMP was markedly attenuated, indicating coupling of the overexpressed EP₃ receptor to inhibitory G proteins (G_i) with constitutive receptor activity. There was no evidence for EP₃ receptor coupling to G_q-mediated protein kinase C signaling. Isolated hearts from tg and wt mice were subjected to 60 minutes of no-flow ischemia and 45 minutes of reperfusion. In tg hearts, ischemic contracture was markedly delayed compared with wt hearts, and the ischemia-induced increase in left ventricular end-diastolic pressure was reduced by 55%. Creatine kinase and lactate dehydrogenase release was significantly decreased by 85% and 73%, respectively, compared with wt hearts.

Conclusions— Constitutive prostaglandin EP₃ receptor signaling exerts a protective effect on cardiomyocytes, which is probably G_i mediated and results in a remarkable attenuation of myocardial injury during ischemia and reperfusion. Cardioprotective actions of E-type prostaglandins may be mediated by this receptor subtype.

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CLINICAL PERSPECTIVE

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