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(Hypertension. 1997;30:1198-1203.)
© 1997 American Heart Association, Inc.
Articles |
Endothelin-1 as an Autocrine/Paracrine Apoptosis Survival Factor for Endothelial Cells
From the Endocrine-Hypertension Division, Second Department of Internal Medicine, Tokyo Medical and Dental University (Japan).
Correspondence to Masayoshi Shichiri, MD, Endocrine-Hypertension Division, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113, Japan. E-mail mshichiri.med2{at}med.tmd.ac.jp
Abstract Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, functions as a potent vasoconstrictor as well as mitogen. We show here a novel role for ET-1 as an apoptosis survival factor for cultured rat endothelial cells. When we rendered endothelial cells obtained from rat aorta quiescent by serum starvation, significant portions of cultured cells underwent apoptotic death as demonstrated by nucleosomal laddering on agarose gel electrophoresis, flow cytometry analysis with FACS, and the TdT-mediated dUTP biotin nick-end labeling (TUNEL) method. ET-1 dose-dependently (10-12 to 10-6 mol/L) suppressed the apoptosis induced by serum starvation. The ETB receptor antagonist (BQ788; 10-6 mol/L) and ETA/B receptor antagonists (PD142893 and PD145065; 10-6 mol/L), but not the ETA receptor antagonist (BQ123; 10-6 mol/L), blocked the apoptosis protective effect of 10-7 mol/L ET-1. Nonimmune rabbit serum reduced the apoptotic event induced by serum deprivation, whereas neutralization of endogenous ET-1 by polyclonal anti–ET-1 antiserum abrogated this protective effect. The ETB receptor antagonist (BQ788; 10-8 to 10-6 mol/L), but not the ETA receptor antagonist (BQ123; 10-8 to 10-6 mol/L), significantly inhibited proliferation of endothelial cells. These data suggest that ET-1, as well as mitogen, functions as an apoptosis survival factor for endothelial cells in an autocrine/paracrine manner via the ETB receptor.
Key Words: endothelin-1 • ETB receptor • cell survival • apoptosis • endothelial cells
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