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.
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.
Authors: Gangjian Qin; Raj Kishore; Christine M Dolan; Marcy Silver; Andrea Wecker; Corinne N Luedemann; Tina Thorne; Allison Hanley; Cynthia Curry; Lindsay Heyd; Deepika Dinesh; Marianne Kearney; Fabio Martelli; Toshinori Murayama; David A Goukassian; Yan Zhu; Douglas W Losordo Journal: Proc Natl Acad Sci U S A Date: 2006-07-11 Impact factor: 11.205
Authors: M Artwohl; T Hölzenbein; L Wagner; A Freudenthaler; W Waldhäusl; S M Baumgartner-Parzer Journal: Br J Pharmacol Date: 2000-12 Impact factor: 8.739
Authors: Saiprasad M Zemse; Chin Wei Chiao; Rob H P Hilgers; R Clinton Webb Journal: Am J Physiol Heart Circ Physiol Date: 2010-07-16 Impact factor: 4.733
Authors: K Frauenstein; U Sydlik; J Tigges; M Majora; C Wiek; H Hanenberg; J Abel; C Esser; E Fritsche; J Krutmann; T Haarmann-Stemmann Journal: Cell Death Differ Date: 2013-08-02 Impact factor: 15.828