Inhibition of MEK1,2/ERK mitogenic pathway by estrogen with antiproliferative properties in rat aortic smooth muscle cells.
Proliferation and migration of vascular smooth muscle cells (VSMCs) are believed to contribute significantly to intimal thickening in atheroscleosis, restenosis, and venous bypass graft disease. Estrogen inhibits proliferation and migration of VSMCs. However, antiproliferative mechanisms of estrogen were not well elucidated yet. In this study, we investigated the antiproliferative effect of estrogen to determine whether the transduction signals and protooncogenes were affected in rat aortic smooth muscle cells (RASMCs). Estrogen inhibited the proliferative response stimulated by 5% fetal bovine serum (FBS) dose-dependently in RASMCs (IC50: 40 nM). In 0.5% serum-treated RASMCs, estrogen dramatically inhibited the activity of extracellular signal-regulated kinases (ERK) followed by inhibition of MEK1,2 activity in dose-dependent manner without affecting the other mitogen-activating protein kinases (MAPKs), c-jun N-terminal kinases (JNK) and p38. Induction of Elk-1 mRNA was significantly reduced dose-dependently up to 100 nM of estrogen. These results indicate that the antiproliferative effects of estrogen in RASMCs involved ERK inhibition followed by the inactivation of MEK1,2 and downregulation of Elk-1 expression.
Hwang
Ki Chul
KC
Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea.
Lee
Kyung Hye
KH
Jang
Yangsoo
Y
D000818:Animals; D001011:Aorta; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D004967:Estrogens; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases