Expression of Nitric Oxide-Transporting Aquaporin-1 Is Controlled by KLF2 and Marks Non-Activated Endothelium In Vivo.
Expression of Nitric Oxide-Transporting Aquaporin-1 Is Controlled by KLF2 and Marks Non-Activated Endothelium In Vivo.
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DOI：
10.1371/journal.pone.0145777
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Horrevoets AJ
中科院分区：
文献类型：
--
作者：
Fontijn RD;Volger OL;van der Pouw-Kraan TC;Doddaballapur A;Leyen T;Baggen JM;Boon RA;Horrevoets AJ
血流反应转录因子kr<s:1>样因子2 （KLF2）维持抗凝血，抗炎内皮与足够的一氧化氮（NO）的生物利用度。在这项研究中，我们旨在探讨在体外和人血管组织中，no转运跨膜孔水通道蛋白-1 （AQP1）的表达及其受动脉粥样硬化保护性KLF2和致动脉粥样硬化炎症刺激的调节。在评估体外KLF2过表达和体内动脉粥样硬化对内皮细胞影响的研究中，通过对基因表达谱的计算机分析，发现AQP1是KLF2下游基因，在无斑块血管壁中表达升高。体外生物力学和药物诱导KLF2的同时也诱导AQP1。染色体免疫沉淀（CHIP）证实KLF2与AQP1启动子结合。内皮细胞的炎症刺激导致AQP1转录受到抑制，而这一抑制受到KLF2过表达的抑制。免疫组织化学显示，水通道蛋白-1在巨噬细胞缺乏的内膜上的非活化内皮中表达，无论这些内膜是无斑块还是含有晚期斑块。我们得出结论，AQP1的表达受klf2介导的动脉粥样硬化保护性剪切应力的正向调节，并且在体外和体内炎症条件下下调。因此，AQP1的内皮表达是动脉粥样硬化保护、非炎症血管壁的特征。我们的数据支持了KLF2在动脉粥样硬化发病前和发病过程中通过eNOS和AQP1的同时表达来稳定血管壁的持续作用。
The flow-responsive transcription factor Krüppel-like factor 2 (KLF2) maintains an anti-coagulant, anti-inflammatory endothelium with sufficient nitric oxide (NO)-bioavailability. In this study, we aimed to explore, both in vitro and in human vascular tissue, expression of the NO-transporting transmembrane pore aquaporin-1 (AQP1) and its regulation by atheroprotective KLF2 and atherogenic inflammatory stimuli. In silico analysis of gene expression profiles from studies that assessed the effects of KLF2 overexpression in vitro and atherosclerosis in vivo on endothelial cells, identifies AQP1 as KLF2 downstream gene with elevated expression in the plaque-free vessel wall. Biomechanical and pharmaceutical induction of KLF2 in vitro is accompanied by induction of AQP1. Chromosome immunoprecipitation (CHIP) confirms binding of KLF2 to the AQP1 promoter. Inflammatory stimulation of endothelial cells leads to repression of AQP1 transcription, which is restrained by KLF2 overexpression. Immunohistochemistry reveals expression of aquaporin-1 in non-activated endothelium overlying macrophage-poor intimae, irrespective whether these intimae are characterized as being plaque-free or as containing advanced plaque. We conclude that AQP1 expression is subject to KLF2-mediated positive regulation by atheroprotective shear stress and is downregulated under inflammatory conditions both in vitro and in vivo. Thus, endothelial expression of AQP1 characterizes the atheroprotected, non-inflamed vessel wall. Our data provide support for a continuous role of KLF2 in stabilizing the vessel wall via co-temporal expression of eNOS and AQP1 both preceding and during the pathogenesis of atherosclerosis.