Caveolin-1-dependent apoptosis induced by fibrin degradation products
Caveolin-1-dependent apoptosis induced by fibrin degradation products
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DOI：
10.1182/blood-2008-07-169433
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发表时间：
2009-04-30
期刊：
影响因子：
20.3
通讯作者：
Weiler, Hartmut
中科院分区：
文献类型：
--
作者：
Guo, Yi-He;Hernandez, Irene;Weiler, Hartmut
在缺乏凝血调节因子血栓调节蛋白的小鼠中，纤维蛋白的纤维蛋白溶解降解产物（FDP）诱导胎盘中的特化细胞类型（多倍体滋养层巨细胞）的凋亡性细胞死亡。在这里，我们证明了FDP的这种生物活性在人FDP中是保守的，不限于滋养层细胞，并且与纤维蛋白片段E（FnE）的A α链片段相关。大多数促凋亡活性是精氨酸-甘氨酸-天冬氨酸（RGD）-独立的，需要小窝蛋白-1依赖性细胞内化FnE。通过小窝的内化由A α 52-81内所含的表位介导，A α 52-81是细胞摄取FnE所必需和足够的。α 52-81本身不引起细胞凋亡，并且竞争性地抑制FnE内化和细胞凋亡诱导。凋亡活性本身存在于A α 17-37内，并且需要通过释放纤维蛋白肽A产生的N-末端新表位。FnE的细胞内化导致线粒体功能的抑制和随后的细胞凋亡，这严格依赖于半胱天冬酶9和3的活性。这些发现描述了一种新机制的分子细节，该机制将纤维蛋白降解与胎盘中的细胞死亡联系起来，这也可能导致与纤维蛋白溶解相关的非胎盘血管床的病理改变。（血。2009; 113：4431-4439）
In mice lacking the blood coagulation regulator thrombomodulin, fibrinolytic degradation products (FDP) of fibrin induce apoptotic cell death of a specialized cell type in the placenta, polyploid trophoblast giant cells. Here, we document that this bioactivity of FDP is conserved in human FDP, is not limited to trophoblast cells, and is associated with an A alpha-chain segment of fibrin fragment E (FnE). The majority of proapoptotic activity is arginine-glycine-aspartic acid (RGD)-independent and requires caveolin-1-dependent cellular internalization of FnE. Internalization through caveoli is mediated by an epitope contained within A alpha 52-81 that is necessary and sufficient for cellular uptake of FnE. A alpha 52-81 does not cause apoptosis itself, and competitively inhibits FnE internalization and apoptosis induction. Apoptotic activity per se resides within A alpha 17-37 and requires the N-terminal neoepitope generated by release of fibrinopeptide A. Cellular internalization of FnE elicits depression of mitochondrial function and consequent apoptosis that is strictly dependent on the activity of caspases 9 and 3. These findings describe the molecular details of a novel mechanism linking fibrin degradation to cell death in the placenta, which may also contribute to pathologic alterations in nonplacental vascular beds that are associated with fibrinolysis. (Blood. 2009; 113: 4431-4439)