Abstract
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 (ETB-R). Although vascular SMC are known to express the ETB-R, its transcriptional regulation has not been studied thus far. Here we demonstrate that the potent inhibitor of nuclear factor κB activation, pyrrolidine dithiocarbamate (PDTC; 30–100 μM), induces de novo ETB-R expression in rat aortic and mesenteric cultured SMC. Electrophoretic mobility shift analyses revealed that besides inhibition of nuclear factor κB, 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 ETB-R expression. The stimulatory effect of PDTC on ETB-R expression was also confirmed functionally by monitoring an enhanced ET-1-induced apoptosis in PDTC-treated cells that was sensitive to the ETB-R antagonist, BQ788. Taken together, these findings demonstrate that C/EBP, GATA-2, and in particular AP-1 can control ETB-R expression in vascular SMC. They further support the notion that ETB-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.
Footnotes
- Received January 10, 2000.
- Accepted June 29, 2000.
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Send reprint requests to: Dr. Markus Hecker, Department of Cardiovascular Physiology, University of Goettingen, Humboldtallee 23, D-37073 Goettingen, Germany. E-mail:hecker{at}veg-physiol.med.uni-goettingen.de
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↵1 On leave from the Department of Clinical Biochemistry, Jagiellonian University College of Medicine, ul. Kopernika 15a, 31-501 Krakow, Poland.
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This work was supported by the Deutsche Forschungsgemeinschaft (project no. He 1587/7-1).
- The American Society for Pharmacology and Experimental Therapeutics
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