Endothelin-1 stimulates DNA synthesis of vascular smooth-muscle cells through transactivation of epidermal growth factor receptor.
To elucidate the molecular mechanism of the mitogenic effect of endothelin-1 (ET-1) on vascular smooth-muscle cells (VSMCs), we studied the effect of AG1478, a novel epidermal growth factor receptor (EGFR) kinase inhibitor, on p42/44 mitogen-activated protein (MAP) kinase activation, c-Fos expression, and DNA synthesis stimulated by ET-1. AG1478 dose-dependently (2.5 x 10(-8) M-2.5 x 10(-7) M) inhibited ET-1-induced MAP kinase activation. The ET-1-induced c-Fos protein expression was inhibited by AG1478 (2.5 x 10(-7) M). AG1478 also dose-dependently inhibited ET-1-stimulated [3H]thymidine incorporation. These data suggest that ET-1 induces MAP kinase activation, c-Fos expression, and promotes proliferation of VSMCs via transactivation of EGFR.
Iwasaki
H
H
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Eguchi
S
S
Marumo
F
F
Hirata
Y
Y
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020032:Tyrphostins
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004247:DNA; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017027:Protein Tyrosine Phosphatases