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|Title:||Stress-induced premature senescence mediated by a novel gene, SENEX, results in an anti-inflammatory phenotype in endothelial cells|
|Citation:||Blood, 2010; 116(19):4016-4024|
|Publisher:||Amer Soc Hematology|
|Paul R. Coleman, Christopher N. Hahn, Matthew Grimshaw, Ying Lu, Xiaochun Li, Peter J. Brautigan, Konstanze Beck, Roland Stocker, Mathew A. Vadas and Jennifer R. Gamble|
|Abstract:||Cellular senescence is a mechanism to inhibit the growth of mammalian cells after oncogenic activation, or in response to damage or stress. We describe here the identification of a novel gene, SENEX, that regulates stress induced premature senescence pathways in endothelial cells (ECs) involving p16(INK4a) and retinoblastoma protein activation. Endogenous levels of SENEX remain unchanged during replicative senescence but are regulated by H(2)O(2)-mediated stress. In contrast to that previously described for senescence in other cell types, the SENEX induced senescent ECs are profoundly anti-inflammatory. The cells are resistant to tumor necrosis factor (TNF)α-induced apoptosis, adhesion of neutrophils and mononuclear cells, and the surface (but not cytoplasmic) expression of endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1. Furthermore they are resistant to thrombin induced vascular leak. Senescent ECs such as those lining atherosclerotic lesions may therefore function to limit the inflammatory response. SENEX is also essential for EC survival since depletion either ectopically by siRNA or by high- dose H(2)O(2) treatment causes apoptosis. Together, these findings expand our understanding of the role of senescence in the vasculature and identify SENEX as a fulcrum for driving the resultant phenotype of the endothelium after activation.|
Tumor Necrosis Factor-alpha
RNA, Small Interfering
Cyclin-Dependent Kinase Inhibitor p16
|Rights:||© 2010 by The American Society of Hematology|
|Appears in Collections:||Aurora harvest|
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