Endothelin-3 regulates endothelin-1 production in cultured human endothelial cells.
Effects of endothelin-3 on the secretion of endothelin-1 and other endothelium-derived substances were investigated in cultured human umbilical vein endothelial cells. The present binding study showed two distinct subpopulations of binding sites for endothelin-3 with higher and lower affinities in cultured human endothelial cells. Endothelin-3 caused an increase in intracellular Ca2+ and inositol 1,4,5-trisphosphate levels and activated protein kinase C in a dose-dependent manner. Endothelin-3 also caused an increase in [3H]thymidine incorporation into cellular DNA and stimulated the production of cyclic guanosine 3',5'-monophosphate, 6-ketoprostaglandin F1 alpha, and immunoreactive endothelin-1 in cultured human endothelial cells. NG-Monomethyl L-arginine (3 x 10(-4) mol/l) and indomethacin (10(-5) mol/l) enhanced endothelin-3-induced endothelin-1 production. These results suggest that endothelin-3 bound to its specific receptors and then caused phosphoinositide breakdown, subsequently mobilizing intracellular Ca2+ and leading to protein kinase C activation and the initiation of DNA synthesis, resulting in the stimulation of endothelin-1 production by human endothelial cells. Furthermore, this endothelin-1 production may be suppressed by endothelium-derived relaxing factor and prostacyclin produced in response to endothelin-3 in cultured human endothelial cells.
Yokokawa
K
K
1st Department of Internal Medicine, Osaka City University Medical School, Japan.
Kohno
M
M
Yasunari
K
K
Murakawa
K
K
Takeda
T
T
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D016232:Endothelins / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D016232:Endothelins; D007295:Inositol Phosphates; D010455:Peptides; D004247:DNA; D011464:Epoprostenol; D011493:Protein Kinase C; D006152:Cyclic GMP; D002118:Calcium