title: Different contributions of STAT3, ERK1/2, and PI3-K signaling to cardiomyocyte hypertrophy by cardiotrophin-1.
abstract: OBJECTIVE
  To assess the contribution of signal transducer and activator of transcription 3 (JAK-STAT3) pathway, extracellular signal-regulated kinases1/2 (ERK1/2) pathway, and phosphatidylinositol 3-kinase (PI3-K) pathway to cardiomyocytes hypertrophy induced by cardiotrophin-1 (CT-1), a new member of interleukin-6 (IL-6) family of cytokines.
  
  
  METHODS
  STAT3, ERK1/2, and PI3-K were assessed by Western blot analysis. Activity of ERK1/2 was also confirmed by in-gel kinase assay. Hypertrophy of cardiomyocyte was evaluated by [3H]leucine incorporation and cellular protein-to-DNA ratio.
  
  
  RESULTS
  CT-1 simultaneously activated phosphorylation of STAT3, ERK1/2, and PI3-K in rat cardiomyocytes. Parthenolide, an inhibitor of STAT, suppressed CT-1-induced [3H]leucine incorporation by 88.3 % and protein-to-DNA ratio by 75.0 %. U0126, an MEK1/2 inhibitor, increased CT-1-induced the phosphorylation of STAT3 in a dose-dependent manner and, consistently, augmented CT-1-induced increase in [3H]leucine incorporation and cellular protein-to-DNA ratio by 17.6 % and 16.3 %, respectively. Wortmannin, a PI3-K inhibitor, did not influence CT-1-induced [3H]leucine incorporation and cellular protein-to-DNA ratio.
  
  
  CONCLUSIONS
  The hypertrophic effect of CT-1 was essentially mediated by STAT3, independent of PI3-K, and negatively regulated by ERK1/2 via inhibiting the phosphorylation of STAT3. The interaction between STAT3 and ERK1/2 in CT-1-induced signaling contributes to development of cardiac hypertrophy.
authors.affiliation: Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China. tianzej@yahoo.com.cn.
authors.forename: Ze-Jun
authors.initials: ZJ
authors.lastname: Tian
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Li
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Hao
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiu-Guang
authors.initials: XG
authors.lastname: Zu
authors.forename: Su-Yun
authors.initials: SY
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: An
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002070:Butadienes / Q000494:pharmacology; D006332:Cardiomegaly / Q000139:chemically induced* / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D007930:Leucine / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002070:Butadienes; D016207:Cytokines; D004268:DNA-Binding Proteins; D007930:Leucine; D048369:MAP Kinase Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; D015534:Trans-Activators; D000077191:Wortmannin; C494088:Stat3 protein, rat; C113580:U 0126; C002669:parthenolide; C092073:cardiotrophin 1