Hypertrophic responses of cardiomyocytes induced by endothelin-1 through the protein kinase C-dependent but Src and Ras-independent pathways.
We have previously shown that endothelin-1 (ET-1) modulates mechanical stretch-induced hypertrophic responses such as extracellular signal-regulated protein kinase (ERK) activation in cardiac myocytes. This study was undertaken to elucidate the ET-1-evoked signal transduction pathways leading to ERK activation. ET-1 was added to cultured cardiac myocytes of neonatal rats with or without a variety of inhibitors. ET-1 activated ERKs, which were followed by an increase in protein synthesis, and inhibition of protein kinase C activities by calphostin C completely suppressed the ET-1-induced ERK activation. We next examined whether tyrosine kinases or Ras are involved in ET-1-induced signaling pathways in cardiomyocytes. Pretreatment with a receptor tyrosine kinase inhibitor did not attenuate ET-1-induced activation of ERKs. Also, co-transfection of the dominant-negative mutant of Ras or active mutant of C-terminal Src kinase, a tyrosine kinase which inhibits Src family tyrosine kinases, with hemagglutinin-tagged ERK2 had no effects on ET-1-induced ERK2 activation. On the other hand, blockade of Raf-1 kinase function by overexpression of the dominant-negative mutant of Raf-1 kinase completely inhibited ET-1-induced ERK2 activation. These results suggest that protein kinase C and Raf-1 kinase, but not Src or Ras, are critical to ET-1-induced ERK activation in cardiac myocytes.
Yamazaki
T
T
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Japan.
Komuro
I
I
Zou
Y
Y
Yazaki
Y
Y
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004247:DNA / Q000276:immunology / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D006321:Heart / Q000502:physiology*; D004676:Myelin Basic Protein / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D010957:Plasmids; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D000596:Amino Acids; D019332:Endothelin-1; D004676:Myelin Basic Protein; D004247:DNA; D019061:src-Family Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D018631:ras Proteins