AJP - Lung Cellular and Molecular Physiology, Vol 269, Issue 2 215-L220, Copyright © 1995 by American Physiological Society
Hypoxia decreases endothelin-1 synthesis by rat lung endothelial cells
B. A. Markewitz, D. E. Kohan and J. R. Michael
Department of Medicine, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
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 h 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.
