Extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells
Extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells
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DOI：
10.1152/ajplung.1997.273.2.l485
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发表时间：
1997-08-01
影响因子：
4.9
通讯作者：
Rounds, S
中科院分区：
文献类型：
--
作者：
Dawicki, DD;Chatterjee, D;Rounds, S
细胞外ATP和腺苷可引起肺动脉内皮细胞凋亡。Am. J.Physiol.273（Lung Cell.摩尔17）：L485-L494，1997年。ATP作为细胞内能量来源和细胞外信号分子。我们报告细胞外ATP引起肺动脉内皮细胞凋亡，评估形态学变化和核小体间DNA降解。我们使用氚标记的可溶性DNA的释放作为细胞凋亡的标记物来研究这种效应的机制。我们的结论是，代谢产物腺苷是负责ATP的凋亡效应，因为核苷酸，可以降解为腺苷，以及腺苷本身，导致DNA损伤，而非代谢的ATP类似物和尿苷5 '-三磷酸是无活性的。此外，外-5 '-核苷酸酶抑制剂α，β-亚甲基-ADP阻断ATP诱导的DNA片段化。腺苷受体激动剂5 '-N-乙基甲酰胺腺苷不引起DNA片段化，腺苷受体拮抗剂不阻断腺苷诱导的细胞凋亡。然而，核苷转运抑制剂潘生丁阻止细胞外ATP诱导的DNA切割。这些发现表明，ATP和腺苷介导的细胞凋亡是通过细胞内事件介导的，而不是通过细胞表面受体。腺苷代谢物肌苷、次黄嘌呤和黄嘌呤不引起细胞凋亡。腺苷类似物3-deazaadenosine和MDL-28842不被代谢，是S-腺苷高半胱氨酸水解酶抑制剂，也会导致DNA断裂。因此，我们推测细胞外ATP和腺苷通过改变需要S-腺苷甲硫氨酸作为甲基供体的甲基化反应引起肺动脉内皮细胞凋亡。我们推测细胞溶解或脱颗粒释放的ATP可能导致内皮细胞死亡。内皮细胞凋亡在急性血管损伤或限制血管生成中可能是重要的。
Extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells. Am. J. Physiol. 273 (Lung Cell. Mol. Physiol. 17): L485-L494, 1997.-ATP acts as an intracellular energy source and an extracellular signaling molecule. We report that extracellular ATP causes apoptosis in pulmonary artery endothelial cells, as assessed by morphological changes and internucleosomal DNA degradation. We investigated the mechanism of this effect using release of tritiated soluble DNA as a marker for apoptosis. We conclude that the metabolite adenosine is responsible for the apoptotic effect of ATP, since nucleotides that can be degraded to adenosine, as well as adenosine itself, cause DNA damage, whereas nonmetabolizable ATP analogs and uridine 5'-triphosphate are inactive. Furthermore, the ecto-5'-nucleotidase inhibitor alpha,beta-methylene-ADP blocks ATP-induced DNA fragmentation. The adenosine receptor agonist 5'-N-ethylcarboxamide adenosine does not cause DNA fragmentation, and adenosine receptor antagonists do not block adenosine-induced apoptosis. However, the nucleoside transport inhibitor dipyridamole prevents extracellular ATP-induced DNA cleavage. These findings indicate that ATP- and adenosine-mediated apoptosis are mediated via intracellular events rather than through cell surface receptor(s). The adenosine 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 inhibitors, also cause DNA fragmentation. Therefore, we speculate that extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells by altering methylation reactions that require S-adenosylmethionine 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.