Hypoxia decreases endothelin-1 synthesis by rat lung endothelial
cells.
Markewitz, Boaz A., Donald E. Kohan, and John R. Michael.
Divisions of Respiratory, Critical Care, and Occupational Pulmonary
Medicine and Nephrology, Department of Medicine, Veterans
Administration Medical Center and University of Utah School of
Medicine, Salt Lake City, Utah 84132
APStracts 2:0061L, 1995.
Endothelin-1 (ET-1) is a 21 amino acid peptide synthesized by several
cell types in the lung. Locally, ET-1 regulates vascular and airway
tone and is mitogenic for vascular and airway smooth muscle cells.
Little, however, is known about the regulation of ET-1 in pulmonary
endothelial cells. Cultured rat lung endothelial cells (RLECs)
release significant amounts of ET-1 into the supernatant and
isolation of RNA followed by reverse transcription and polymerase
chain reaction amplification confirms the presence of ET-1 mRNA.
Exposure of RLECs to a hypoxic environment for 24 hours decreases ET
-1 production by approximately 50% compared with normoxic controls.
The effect of hypoxia is reversible upon restoration of a normoxic
environment. RNase protection studies reveal decreased ET-1 mRNA in
hypoxic cells. Inhibition of nitric oxide (NO) synthase increases ET
-1 synthesis during normoxia and hypoxia without altering the
inhibitory effect of hypoxia. The addition of 10% carbon monoxide
(CO) to the hypoxic environment does not erase the effect of hypoxia
on ET-1 production, suggesting that the transduction process does not
involve a heme-sensor. In summary, we conclude that: 1) RLECs
synthesize ET-1; 2) hypoxia reversibly decreases ET-1 production; 3)
constitutive NO production decreases ET-1 release during normoxia and
hypoxia; 4) inhibiting constitutive NO synthesis does not prevent the
decrease in ET-1 release caused by hypoxia; and 5) this effect of
hypoxia appears to be transduced without the involvement of a heme
-sensor.
Received 28 September 1994; accepted in final form 7 April 1995.
APS Manuscript Number L285-4.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 25 April 1995.