Restoration of E2F expression rescues vascular endothelial cells from tumor necrosis factor-alpha-induced apoptosis.
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.[1]References
- Restoration of E2F expression rescues vascular endothelial cells from tumor necrosis factor-alpha-induced apoptosis. Spyridopoulos, I., Principe, N., Krasinski, K.L., Xu, S.h., Kearney, M., Magner, M., Isner, J.M., Losordo, D.W. Circulation (1998) [Pubmed]
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