Decoy oligodeoxynucleotide characterization of transcription factors controlling endothelin-B receptor expression in vascular smooth muscle cells.
Endothelin-1 is not only a powerful vasoconstrictor but also a potent mitogen for vascular smooth muscle cells (SMC), acting through both the endothelin-A and endothelin-B receptor (ET(B)-R). Although vascular SMC are known to express the ET(B)-R, its transcriptional regulation has not been studied thus far. Here we demonstrate that the potent inhibitor of nuclear factor kappaB activation, pyrrolidine dithiocarbamate (PDTC; 30-100 microM), induces de novo ET(B)-R expression in rat aortic and mesenteric cultured SMC. Electrophoretic mobility shift analyses revealed that besides inhibition of nuclear factor kappaB, PDTC enhances activator protein-1 (AP-1), CCAAT/enhancer-binding protein (C/EBP), and GATA-2 activity in these cells. Preincubation of PDTC-stimulated cells with appropriate decoy oligodeoxynucleotides confirmed the involvement of these three transcription factors, namely that of AP-1, in ET(B)-R expression. The stimulatory effect of PDTC on ET(B)-R expression was also confirmed functionally by monitoring an enhanced ET-1-induced apoptosis in PDTC-treated cells that was sensitive to the ET(B)-R antagonist, BQ788. Taken together, these findings demonstrate that C/EBP, GATA-2, and in particular AP-1 can control ET(B)-R expression in vascular SMC. They further support the notion that ET(B)-R expression in these cells may play an important role in cardiovascular complications, such as restenosis following angioplasty that in the early phase is characterized by prominent SMC apoptosis.
Wagner
A H
AH
Department of Cardiovascular Physiology, University of Goettingen, Germany.
Krzesz
R
R
Gao
D
D
Schroeder
C
C
Cattaruzza
M
M
Hecker
M
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000235:genetics*; D013859:Thiocarbamates / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D000975:Antioxidants; D009838:Oligodeoxyribonucleotides; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013859:Thiocarbamates; D014157:Transcription Factors; C020972:pyrrolidine dithiocarbamic acid