Epidermal growth factor induces hypertrophic responses and Stat5 activation in rat ventricular cardiomyocytes.
Epidermal growth factor (EGF) was tested for its ability to promote hypertrophic responses in neonatal rat ventricular cardiomyocytes. Exposure of these cells to 100 n m EGF for 2-18 h resulted in a time-dependent increase in protein synthesis reaching 174+/-18% of control values at 18 h. After 30 min stimulation, the mRNA levels of c-jun and c-fos were also increased 20- and 36-fold, respectively. We also investigated EGF-induced activation of Stat (signal transducers and activators of transcription) proteins as well as the possible interactions of this signaling pathway with the p38 and p42/44 MAP kinases cascades. EGF did not activate Stat1 and Stat3, but did induce a rapid and transient activation of Stat5, which corresponded mainly to Stat5b DNA-binding. The EGF-promoted Stat5 DNA-binding was decreased in a concentration-dependent manner by the p38 MAPK inhibitor SB 203580 (IC(50)=1.2 microm), whereas it was tripled by 50 micro m PD 98059, an inhibitor of the p42/44 MAPK cascade. This is the first demonstration that EGF increases protein synthesis and early response gene expression in cardiomyocytes, responses considered as markers of hypertrophy in these cells. The results further show that EGF activates Stat5, that this response requires p38 MAPK stimulation, and it is negatively modulated by p42/44 MAPK.
Rebsamen
M C
MC
Division of Endocrinology and Diabetology, Division of Immunology and Allergy, Geneva 14, CH-1211, Switzerland.
Arrighi
J F
JF
Juge-Aubry
C E
CE
Vallotton
M B
MB
Lang
U
U
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; C494097:Stat5b protein, rat; D015534:Trans-Activators; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases