Restoration of E2F expression rescues vascular endothelial cells from tumor necrosis factor-α-induced apoptosis
Restoration of E2F expression rescues vascular endothelial cells from tumor necrosis factor-α-induced apoptosis
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DOI：
10.1161/01.cir.98.25.2883
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发表时间：
1998-12-22
期刊：
影响因子：
37.8
通讯作者：
Losordo, DW
中科院分区：
文献类型：
--
作者：
Spyridopoulos, I;Principe, N;Losordo, DW
背景-正常情况下，静止的内皮细胞（EC）排列在动脉的内表面，防止血栓形成和新生内膜生长。各种有害刺激，包括球囊血管成形术，可能会损害EC的完整性，从而启动增殖并触发局部释放细胞因子，包括肿瘤坏死因子-α（TNF-α）。方法和结果-使用可溶性受体分子体内阻断TNF-α导致在球囊血管成形术部位加速的再内皮化，提示TNF-α在减弱球囊血管成形术后内皮再生中的重要生理作用。我们的研究表明，TNF-α，一种凋亡诱导细胞因子，可诱导增殖期EC发生G1期细胞周期阻滞，与增殖期EC相比，静止期EC对TNF诱导的凋亡相对免疫，其表现出与TNF诱导的凋亡和细胞周期阻滞一致的E2 F转录因子的抑制。我们还表明，在这种情况下，E2 F过表达产生的生存效应在增殖EC和恢复细胞周期的进展，在直接对比的结果，以前的报告，这表明，E2 F在正常的周期细胞的表达失调诱导apoptosis. Conclusions这些数据表明，TNF诱导的细胞凋亡是高度依赖于细胞周期的活动，E2 F可以作为生存因子在一定条件下。
Background-Normally, quiescent endothelial cells (EC) line the inner surface of arteries and protect against thrombosis and neointimal growth. A variety of noxious stimuli, including balloon angioplasty, may compromise EC integrity, thereby initiating proliferation and triggering the local release of cytokines, including tumor necrosis factor-alpha (TNF-alpha).Methods and Results-In vivo blockade of TNF-alpha using a soluble receptor molecule results in accelerated reendothelialization at sites of balloon angioplasty, suggesting an important physiological role of TNF-alpha in attenuating regrowth of endothelium after balloon angioplasty. Our studies reveal that TNF-alpha, an apoptosis-inducing cytokine, induces G1 cell-cycle arrest in proliferating EC, Quiescent EC are relatively immune to TNF-induced apoptosis versus proliferating EC, which display repression of the E2F transcription factor coincident with TNF-induced apoptosis and cell-cycle arrest. We also show that in this setting, E2F overexpression exerts a survival effect in proliferating EC and restores cell-cycle progression, in direct contrast to results of prior reports, which revealed that deregulated expression of E2F in normally cycling cells induces apoptosis.Conclusions-These data demonstrate that TNF-induced apoptosis is highly dependent on cell-cycle activity and that E2F can function as survival factor under certain conditions.