Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes.
Activation of glycoprotein (gp) 130 transduces hypertrophic and cytoprotective signals in cardiac myocytes. In the present study, we have demonstrated that signals through gp130 increase the expression of vascular endothelial growth factor (VEGF) in cardiac myocytes via the signal transducer and activator of transcription (STAT) 3 pathway. After activation of gp130 with leukemia inhibitory factor (LIF), expression of VEGF mRNA rapidly increased with a peak at 3 h in cultured cardiac myocytes. Cardiotrophin-1 also enhanced VEGF mRNA expression in a dose-dependent manner. VEGF protein production and secretion to the medium were also enhanced by LIF and cardiotrophin-1 but not by interleukin-6. Adenovirus transfer of the dominant-negative form of STAT3 to cultured cardiac myocytes inhibited induction of VEGF expression induced by LIF, but neither PD98059 nor wortmannin was affected. In murine hearts, intravenous administration of LIF augmented expression of VEGF mRNA; however, the hearts of transgenic mice overexpressing dominant-negative STAT3 showed reduced expression of VEGF mRNA that was not induced after LIF stimulation. These data provide the first evidence that a STAT family protein functions as a regulator of angiogenic growth factors and suggest that gp130/STAT signaling in cardiac myocytes can control vessel growth during cardiac remodeling.
Funamoto
M
M
Department of Molecular Medicine, Osaka University Medical School, Osaka University, Suita Osaka 565-0871, Japan.
Fujio
Y
Y
Kunisada
K
K
Negoro
S
S
Tone
E
E
Osugi
T
T
Hirota
H
H
Izumi
M
M
Yoshizaki
K
K
Walsh
K
K
Kishimoto
T
T
Yamauchi-Takihara
K
K
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D006131:Growth Inhibitors; C494200:Il6st protein, mouse; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D050822:Cytokine Receptor gp130; C092073:cardiotrophin 1