Stress-induced premature senescence mediated by a novel gene, SENEX, results in an anti-inflammatory phenotype in endothelial cells
Stress-induced premature senescence mediated by a novel gene, SENEX, results in an anti-inflammatory phenotype in endothelial cells
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DOI：
10.1182/blood-2009-11-252700
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发表时间：
2010-11-11
期刊：
影响因子：
20.3
通讯作者：
Gamble, Jennifer R.
中科院分区：
文献类型：
--
作者：
Coleman, Paul R.;Hahn, Christopher N.;Gamble, Jennifer R.
细胞衰老是在致癌激活后或响应于损伤或应激而抑制哺乳动物细胞生长的机制。我们在这里描述了一种新的基因，SENEX，调节压力诱导的过早衰老途径在内皮细胞（ECs）涉及p16（INK4a）和视网膜母细胞瘤蛋白激活的鉴定。SENEX的内源性水平在复制衰老过程中保持不变，但受到H2O2介导的应激的调节。与先前描述的其他细胞类型中的衰老相反，SENEX诱导的衰老EC具有显著的抗炎性。这些细胞对肿瘤坏死因子（TNF）α诱导的细胞凋亡、中性粒细胞和单核细胞的粘附以及内皮白细胞粘附分子1和血管细胞粘附分子1的表面（而非细胞质）表达具有抗性。此外，它们对凝血酶诱导的血管渗漏具有抗性。衰老的内皮细胞，如那些内衬动脉粥样硬化病变，因此可能起到限制炎症反应。SENEX对于EC存活也是必不可少的，因为siRNA或高剂量H2O2处理的异位消耗引起细胞凋亡。总之，这些发现扩展了我们对血管系统中衰老作用的理解，并将SENEX确定为激活后驱动内皮细胞表型的支点。（Blood.2010; 116（19）：4016 - 4024）
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 retino-blastoma protein activation. Endogenous levels of SENEX remain unchanged during replicative senescence but are regulated by H2O2-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)alpha-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 H2O2 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. (Blood.2010;116(19):4016-4024)