title: Cardiospecific overexpression of the prostaglandin EP3 receptor attenuates ischemia-induced myocardial injury.
abstract: 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 Gi-coupled EP3 subtype.
  
  
  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 (Gi) with constitutive receptor activity. There was no evidence for EP3 receptor coupling to Gq-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 Gi 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.
authors: Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Moorenstr 5, D-40225 Düsseldorf, Germany.
authors: Melanie
authors: M
authors: Martin
authors: Jutta
authors: J
authors: Meyer-Kirchrath
authors: Gernot
authors: G
authors: Kaber
authors: Christoph
authors: C
authors: Jacoby
authors: Ulrich
authors: U
authors: Flögel
authors: Jürgen
authors: J
authors: Schrader
authors: Ulrich
authors: U
authors: Rüther
authors: Karsten
authors: K
authors: Schrör
authors: Thomas
authors: T
authors: Hohlfeld
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011493:Protein Kinase C / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D019076:Transgenes; D016277:Ventricular Function, Left
chemical_list: D000319:Adrenergic beta-Antagonists; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go