title: Prostaglandin E2 activates Stat3 in neonatal rat ventricular cardiomyocytes: A role in cardiac hypertrophy.
abstract: OBJECTIVE
  The purpose of this study was to investigate whether prostaglandin E2 (PGE2) induces Signal transducer and activator of transcription 3 (Stat3) activation in neonatal rat ventricular cardiomyocytes and if so to determine the possible role of this activation in PGE2-induced hypertrophic responses.
  
  
  METHODS
  Stat3 activation and its nuclear phosphorylation were determined by electrophoretic mobility shift assay (EMSA) and by Western blots, respectively. Protein synthesis was assessed by [3H]-leucine incorporation into total protein and cell surface was quantified by microscopic analysis.
  
  
  RESULTS
  We found that PGE2 induces a concentration- (1-100 nM) and time-dependent increase in Stat3 activation, reaching maximal values after 90 min of stimulation. Experiments with agonists and antagonists of the PGE2 receptor subtypes EP1-EP4 indicate that PGE2 activates Stat3 mainly through the EP4 receptor. We further observed that the extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126 abolishes PGE2-induced Stat3 activation whereas the p38 MAP kinase blocker SB203580 has no effect. Nuclear Stat3 phosphorylation induced by PGE2 is also suppressed by the translation and transcription inhibitors, cycloheximide and actinomycin D, respectively. Transfecting ventricular cardiomyocytes with a small interfering RNA (siRNA) targeting rat Stat3, we obtained an approximately 70% reduction in Stat3 expression, 24 and 48 h after electroporation. In these Stat3-silenced cells, the PGE2-induced increase in protein synthesis and cell surface is strongly inhibited.
  
  
  CONCLUSIONS
  In ventricular cardiomyocytes, PGE2 induces the activation of Stat3 which plays an essential role in PGE2-induced increase in cell size and protein synthesis. The activation of Stat3 occurs mainly through EP4 and involves ERK1/2 as well as newly synthesized protein(s).
authors.affiliation: Division of Endocrinology, Diabetology and Nutrition, University Hospital, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. Miguel.Frias@medecine.unige.ch
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Frias
authors.forename: Michela C
authors.initials: MC
authors.lastname: Rebsamen
authors.forename: Christine
authors.initials: C
authors.lastname: Gerber-Wicht
authors.forename: Ursula
authors.initials: U
authors.lastname: Lang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002070:Butadienes / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020868:Gene Silencing; D019833:Genistein / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009570:Nitriles; D011500:Protein Synthesis Inhibitors; C545652:Ptger4 protein, rat; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor; C113580:U 0126; D003609:Dactinomycin; D003513:Cycloheximide; D019833:Genistein; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; C093642:SB 203580