Prolonged shear stress and KLF2 suppress constitutive proinflarnmatory transcription through inhibition of ATF2
Prolonged shear stress and KLF2 suppress constitutive proinflarnmatory transcription through inhibition of ATF2
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DOI：
10.1182/blood-2006-07-036020
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发表时间：
2007-05-15
期刊：
影响因子：
20.3
通讯作者：
Horrevoets, Anton J. G.
中科院分区：
文献类型：
--
作者：
Fledderus, Joost O.;van Thienen, Johannes V.;Horrevoets, Anton J. G.
由于动脉分叉和弯曲处的血流紊乱而导致的剪切应力的缺乏导致内皮功能障碍和促炎基因表达，最终导致动脉粥样硬化形成。KLF 2最近被认为是一种转录因子，参与介导血流的抗炎作用。我们研究了剪切对人脐静脉内皮细胞（HUVECs）基础和TNF-α诱导的全基因组表达谱的影响。聚类分析证实，剪切应力诱导表达的保护基因，包括KLF 2，eNOS，和血栓调节蛋白，而基础表达的TNF-α反应基因适度下降。这些基因的启动子分析显示ATF转录因子的结合位点富集，而TNF-α诱导的基因表达主要依赖于NF-κ B。此外，覆盖动脉粥样硬化斑块的人内皮细胞与未受影响部位的内皮细胞相比，磷酸化核ATF 2的数量增加。在HUVECs中，在剪切下观察到ATF 2的核结合活性显著降低，并且似乎是KLF 2依赖性的。在无流动条件下，用siRNA减少ATF 2有效地抑制了基础促炎基因表达。总之，我们证明，剪切应力和KLF 2抑制核活性的ATF 2，提供了一个潜在的机制，暴露于层流的内皮细胞受到保护，从基础促炎，致动脉粥样硬化基因表达。
Absence of shear stress due to disturbed blood flow at arterial bifurcations and curvatures leads to endothelial dysfunction and proinflammatory gene expression, ultimately resulting in atherogenesis. KLF2 has recently been implicated as a transcription factor involved in mediating the anti-inflammatory effects of flow. We investigated the effect of shear on basal and TNF-alpha-induced genomewide expression profiles of human umbilical vein endothelial cells (HUVECs). Cluster analysis confirmed that shear stress induces expression of protective genes including KLF2, eNOS, and thrombomodulin, whereas basal expression of TNF-alpha-responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF-alpha-induced gene expression was mostly NF-kappa B dependent. Furthermore, human endothelial cells overlying atherosclerotic plaques had increased amounts of phosphorylated nuclear ATF2 compared with endothelium at unaffected sites. In HUVECs, a dramatic reduction of nuclear binding activity of ATF2 was observed under shear and appeared to be KLF2 dependent. Reduction of ATF2 with siRNA potently suppressed basal proinflammatory gene expression under no-flow conditions. In conclusion, we demonstrate that shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expression.