Ba. Markewitz et al., HYPOXIA DECREASES ENDOTHELIN-1 SYNTHESIS BY RAT LUNG ENDOTHELIAL-CELLS, American journal of physiology. Lung cellular and molecular physiology, 13(2), 1995, pp. 215-220
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 to
ne and is mitogenic for vascular and airway smooth muscle cells. Littl
e, however, is known about the regulation of ET-1 in pulmonary endothe
lial cells. Cultured rat lung endothelial cells (RLECs) release signif
icant amounts of ET-1 into the supernatant, and isolation of RNA follo
wed by reverse transcription and polymer ase chain reaction amplificat
ion confirms the presence of ET-1 mRNA. Exposure of RLECs to a hypoxic
environment for 24 h decreases ET-1 production by similar to 50% comp
ared 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 (GO) 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) c
onstitutive NO production decreases ET-1 release during normoxia and h
ypoxia; 4) inhibiting constitutive NO synthesis does not prevent the d
ecrease in ET-1 release caused by hypoxia; and 5) this effect of hypox
ia appears to be transduced without the involvement of a heme sensor.