EXTRACELLULAR ATP AND ADENOSINE CAUSE APOPTOSIS OF PULMONARY-ARTERY ENDOTHELIAL-CELLS

Extracellular ATP and adenosine cause apoptosis of pulmonary artery en dothelial cells. Am. J. Physiol. 273 (Lung Cell. Mol. Physiol. 17): L4 85-L494, 1997.-ATP acts as an intracellular energy source and an extra cellular signaling molecule. We report that extracellular ATP causes a poptosis in pulmonary artery endothelial cells, as assessed by morphol ogical changes and internucleosomal DNA degradation. We investigated t he mechanism of this effect using release of tritiated soluble DNA as a marker for apoptosis. We conclude that the metabolite adenosine is r esponsible for the apoptotic effect of ATP, since nucleotides that can be degraded to adenosine, as well as adenosine itself, cause DNA dama ge, whereas nonmetabolizable ATP analogs and uridine 5'-triphosphate a re inactive. Furthermore, the ecto-5'-nucleotidase inhibitor alpha,bet a-methylene-ADP blocks ATP-induced DNA fragmentation. The adenosine re ceptor agonist 5'-N-ethylcarboxamide adenosine does not cause DNA frag mentation, and adenosine receptor antagonists do not block adenosine-i nduced apoptosis. However, the nucleoside transport inhibitor dipyrida mole prevents extracellular ATP-induced DNA cleavage. These findings i ndicate that ATP- and adenosine-mediated apoptosis are mediated via in tracellular events rather than through cell surface receptor(s). The a denosine metabolites inosine, hypoxanthine, and xanthine do not cause apoptosis. The adenosine analogs 3-deazaadenosine and MDL-28842, which are not metabolized and are S-adenosylhomocysteine hydrolase inhibito rs, also cause DNA fragmentation. Therefore, we speculate that extrace llular ATP and adenosine cause apoptosis of pulmonary artery endotheli al cells by altering methylation reactions that require S-adenosylmeth ionine as the methyl donor. We speculate that ATP released from cells undergoing cytolysis or degranulation may cause endothelial cell death . Endothelial cell apoptosis may be important in acute vascular injury or in limiting angiogenesis.