Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2)
Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2)
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DOI：
10.1182/blood-2002-01-0046
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发表时间：
2002-09-01
期刊：
影响因子：
20.3
通讯作者：
Horrevoets, AJG
中科院分区：
文献类型：
--
作者：
Dekker, RJ;van Soest, S;Horrevoets, AJG
内皮细胞在生物力学力的明显转录控制下表达大量基因，其中许多既不是细胞类型也不是流动特异性的。我们着手识别人类血管内皮细胞中独特的流动响应基因。使用商业DNA微阵列进行的转录谱分析确定了18000个基因中的12个，这些基因在稳定层流（25达因/ cm（2））24小时后至少被调节了5倍。在暴露于单向脉动流（19 +/- 12 dyne/cm（2））7天后，12例患者中只有3例仍升高至少5倍。构建了约300个血管细胞相关基因片段的定制微阵列，并且表达分析揭示了许多流动诱导的基因也由以下试剂中的至少一种诱导：肿瘤坏死因子-α（TNF-α）、白细胞介素-1 β（IL-1 β）、转化生长因子-β、血管内皮生长因子或凝血酶，表明在适应性或应激反应中的更普遍的作用。大多数流量诱导基因也受到TNF-α的诱导，但不受IL-1 β的诱导，这表明活性氧簇的参与。确定了一组有限的基因，这些基因对于暴露于流动的培养物是独特的，包括肺Kruppel样因子（LKLF/KLF 2）和细胞色素P450 1B 1（CYP 1B 1）。与此形成鲜明对比的是，这两个基因基本上被TNF-α抑制。用原位杂交法检测到LKLF mRNA仅存在于健康人主动脉血管内皮细胞中，但未检测到CYP 1B 1 mRNA，且LKLF似乎具有流量调节作用。到目前为止，LKLF是第一个内皮细胞转录因子，这是唯一诱导的流量，因此可能是在生理健康的分子基础上，流量暴露状态的内皮细胞。(C)2002年，美国血液学会。
The endothellum expresses a large repertoire of genes under apparent transcriptional control of biomechanical forces, many of which are neither cell-type nor flow specific. We set out to identify genes that are uniquely flow responsive in human vascular endothelial cells. Transcriptional profiling using commercial DNA microarrays identified 12 of 18 000 genes that were modulated at least 5-fold after 24 hours of steady laminar flow (25 dyne/ cm(2)). After a 7-day exposure to unidirectional pulsatile flow (19 +/- 12 dyne/cm(2)), only 3 of 12 remained elevated at least 5-fold. A custom microarray of -300 vascular cell-related gene fragments was constructed, and expression analysis revealed that many flow-induced genes are also induced by at least one of the following agents: tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), transforming growth factor-beta, vascular endothelial growth factor, or thrombin, indicating a more general role in adaptive or stress responses. Most flow-induced genes were also induced by TNF-alpha but not IL-1beta, suggesting the involvement of reactive oxygen species. A limited panel of genes that are unique for flow-exposed cultures was identified, including lung Kruppel-like factor (LKLF/KLF2) and cytochrome P450 1B1 (CYP1B1). In marked contrast, both these genes were substantially repressed by TNF-alpha. LKLF but not CYP1B1 mRNA was detected exclusively in the vascular endothelium of healthy human aorta by in situ hybridization and appeared to-be flow regulated. To date LKLF is the first endothelial transcription factor that is uniquely induced by flow and might therefore be at the molecular basis of the physiological healthy, flow-exposed state of the endothelial cell. (C) 2002 by The American Society of Hematology.