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Am J Physiol Lung Cell Mol Physiol 275: L379-L388, 1998;
1040-0605/98 $5.00
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Vol. 275, Issue 2, L379-L388, August 1998

Mechanism of extracellular ATP- and adenosine-induced apoptosis of cultured pulmonary artery endothelial cells

Sharon Rounds1, Winnie Lin Yee2, Doloretta D. Dawicki1, Elizabeth Harrington1, Nancy Parks1, and Michael V. Cutaia1

1 Pulmonary and Critical Care Medicine Section, Providence Veterans Affairs Medical Center, Brown University School of Medicine, Providence, Rhode Island 02908; and 2 Department of Chemistry, University of Connecticut, West Hartford, Connecticut 06117

Apoptosis may be important in the exacerbation of endothelial cell injury or limitation of endothelial cell proliferation. We have found that extracellular ATP (exATP) and adenosine cause endothelial apoptosis and that the development of apoptosis is linked to intracellular metabolism of adenosine [Dawicki, D. D., D. Chatterjee, J. Wyche, and S. Rounds. Am. J. Physiol. 273 (Lung Cell Mol. Physiol. 17): L485-L494, 1997]. In the present study, we investigated the mechanism of this effect. We found that exATP, adenosine, and the S-adenosyl-L-homocysteine (SAH) hydrolase inhibitor MDL-28842 caused apoptosis and decreased the ratio of S-adenosyl-L-methionine to SAH compared with untreated control cells. Using release of soluble [3H]thymidine as a measure of DNA fragmentation, we found that the effect of adenosine on soluble DNA release was potentiated by coincubation with homocysteine. These results suggest that the mechanism of exATP- and adenosine-induced endothelial cell apoptosis involves inhibition of SAH hydrolase. exATP-induced apoptosis was enhanced by an inhibitor of adenosine deaminase, whereas exogenous adenosine-induced apoptosis was partially inhibited by an adenosine deaminase inhibitor. These results suggest that adenosine deaminase may also be involved in the mechanism of adenosine-induced endothelial cell apoptosis. Adenosine and MDL-28842 caused intracellular acidosis as assessed with the fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. The cell-permeant base chloroquine prevented adenosine-induced acidosis but not apoptosis. Thus, although intracellular acidosis is associated with adenosine-induced apoptosis, it is not necessary for this effect. We speculate that exATP- and adenosine-induced endothelial cell apoptosis may be due to an inhibition of methyltransferase(s) activity. Purine-induced endothelial cell apoptosis may be important in limiting endothelial cell proliferation after vascular injury.

adenosine 5'-triphosphate; S-adenosyl-L-homocysteine; S-adenosyl-L-methionine; S-adenosyl-L-homocysteine hydrolase; methyltransferase; adenosine kinase; adenosine deaminase; acidosis; sodium/hydrogen antiport; nitric oxide


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