Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes.
BACKGROUND
gp130, a signal transducer of the IL-6-related cytokines, is expressed ubiquitously, including in the heart. The activation of gp130 in cardiac myocytes was reported to induce myocardial hypertrophy. The downstream side of gp130 consists of two distinct pathways in cardiac myocytes, one a Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, the other a mitogen-activated protein kinase (MAPK) pathway. In the present study, we examined whether the JAK/STAT pathway, especially the STAT3-mediated pathway, plays a critical role in gp130-dependent myocardial hypertrophy by transfecting wild-type and mutated-type STAT3 cDNA to cardiac myocytes.


RESULTS
We constructed three kinds of replication-defective adenovirus vectors carrying wild-type (AD/WT) or mutated-type (AD/DN) STAT3 cDNA or adenovirus vector itself (AD). Cultured murine cardiac myocytes infected with adenovirus were stimulated with leukemia inhibitory factor (LIF), and the expression of c-fos and atrial natriuretic factor (ANF) mRNAs and [3H]leucine incorporation were examined. There were no significant differences in MAPK activity among the three groups. Compared with AD-transfected cardiac myocytes, induction of c-fos and ANF mRNAs and protein synthesis after LIF stimulation were significantly augmented in AD/WT-transfected cells. In contrast, induction of c-fos and ANF mRNA expression and protein synthesis were attenuated after LIF stimulation in cardiac myocytes transfected with AD/DN.


CONCLUSIONS
These results suggest that the STAT3-dependent signaling pathway downstream of gp 130 promotes cardiac myocyte hypertrophy under stimulation with LIF.
Kunisada
K
K
Department of Medicine III, Osaka University Medical School, Suita, Japan.
Tone
E
E
Fujio
Y
Y
Matsui
H
H
Yamauchi-Takihara
K
K
Kishimoto
T
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology* / Q000503:physiopathology; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005822:Genetic Vectors; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6; D007930:Leucine / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C494200:Il6st protein, mouse; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D008562:Membrane Glycoproteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D014443:Tyrosine; D009320:Atrial Natriuretic Factor; D007930:Leucine