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Endothelin B Receptor Antagonist Increases Preproendothelin-1 Transcription in Bovine Aortic Endothelial Cells and In Vivo

Peled, Michael* † ‡; Shaish, Aviv PhD* ‡; Frishman, Liron* ‡; Cohen, Hofit MD* †; Tal, Reshef* ‡; Harats, Dror MD* ‡

Journal of Cardiovascular Pharmacology:
doi: 10.1097/01.fjc.0000211755.54691.ba
Original Articles
Abstract

Endothelin-1 (ET-1) receptor antagonists increase plasma immunoreactive ET-1 levels. However, their effect on preproendothelin-1 (PPE-1) mRNA levels is still controversial. Few studies have found a decrease in PPE-1 mRNA levels in endothelial cells treated with the nonselective ETA/B receptor antagonist, and others demonstrated that an ETB blockade by the selective antagonist BQ788 increases PPE-1 mRNA levels. We studied the effect of ETA and ETB selective receptor antagonists on PPE-1 transcription, both in vitro and in vivo. Endothelial cells, transiently transfected with PPE-1 luciferase plasmid, were treated with ET-1 receptor antagonists. Bosentan, a dual ETA/B receptor antagonist, and BQ788 (ETB receptor antagonist) treatment resulted in a 1.6-fold and 1.3-fold increase, respectively in luciferase activity as compared with the untreated control. In contrast, the ETA receptor antagonist, BQ123, had no effect on luciferase activity. Transgenic mice that express the luciferase gene under the control of PPE-1 promoter were treated with Bosentan. Luciferase activity, PPE-1 mRNA levels, and plasma immunoreactive ET-1 levels were increased by 1.6-fold to 2.0-fold in the Bosentan-treated group compared with the untreated, control group. ET-1 receptor blockade increased PPE-1 transcription both in vitro and in vivo. The increased transcription can be attributed to ETB receptor blockade, because BQ-788, but not BQ-123, increased PPE-1 transcription.

Author Information

*Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer

Sackler School of Medicine, Tel Aviv University, Tel Aviv

Vascular Biogenics Ltd, Or Yehuda, Israel

Reprints: Prof Dror Harats, MD, Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel-Hashomer 52621, Israel (e-mail: dharats@post.tau.ac.il).

Received for publication December 25, 2005; accepted February 22, 2006

This work was carried out as a part of thesis work by M. Peled in the Sackler Faculty of Medicine, Tel Aviv University.

© 2006 Lippincott Williams & Wilkins, Inc.