title: Cardiotrophin-1 and urocortin cause protection by the same pathway and hypertrophy via distinct pathways in cardiac myocytes.
abstract: Cardiotrophin-1 (CT-1) is an Interleukin-6 family cytokine with known hypertrophic and protective effects in cardiac cells. CT-1 and the corticotrophin releasing hormone-like hormone urocortin protect cardiac myocytes by the same p42/44 mitogen activated protein kinase (p42/44 MAPK) dependent pathway. We investigated whether urocortin is also hypertrophic in cardiac myocytes and whether it shares a common pathway with CT-1 for this effect. Moreover, we also investigated, for the first time whether CT-1 and urocortin can induce hypertrophy in cultured adult as opposed to neonatal cardiac cells. Urocortin and CT-1 caused hypertrophy (as measured by an increase in cell area and enhanced protein: DNA ratio) in both adult and neonatal rat cultured cardiac myocytes. The hypertrophic effect of CT-1 was dependent on the signal transducer and activator of transcription 3 (STAT3) pathway but the hypertrophic effect of urocortin was independent of this pathway. In contrast, inhibition of the protective p42/p44 MAPK pathway has no effect on the hypertrophic effect of CT-1 or urocortin. Additionally, inhibition of the STAT3 pathway has no effect on the protective effect of CT-1 or urocortin. These results identify urocortin as a novel hypertrophic and protective agent whose hypertrophic effect is mediated by a distinct pathway to that activated by CT-1, although the two factors mediate protection via the same pathway.
authors.affiliation: Medical Molecular Biology Unit, University College London, 30 Guilford Street, London, WC1N 1EH, UK. d.latchman@ich.ucl.ac.uk
authors.forename: Julia E
authors.initials: JE
authors.lastname: Railson
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liao
authors.forename: Bhawanjit K
authors.initials: BK
authors.lastname: Brar
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Buddle
authors.forename: Diane
authors.initials: D
authors.lastname: Pennica
authors.forename: Anastasis
authors.initials: A
authors.lastname: Stephanou
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005799:Genes, Dominant; D006984:Hypertrophy; D020287:In Situ Nick-End Labeling; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D018696:Neuroprotective Agents; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D054832:Urocortins
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D018696:Neuroprotective Agents; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D054832:Urocortins; D004247:DNA; D003346:Corticotropin-Releasing Hormone; C092073:cardiotrophin 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases