HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia.
HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia.
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HIF-1依赖性抑制缺氧中平衡性核苷转运蛋白（ENT）。
DOI：
10.1084/jem.20050177
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发表时间：
2005-12-05
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细胞外腺苷（Ado）在有限氧可用性（缺氧）条件下被认为是中枢信号分子，调节如血管渗漏、白细胞活化和积聚等多种生理结果。目前，缺氧时细胞外Ado升高的分子机制尚不清楚。在本研究中，我们追求的假设，减少摄取的Ado有效地增强细胞外Ado信号。最初的研究表明，Ado的半衰期在内皮细胞暴露于缺氧后增加多达五倍。对平衡型核苷转运蛋白（ENT）1和ENT 2的表达水平的检测显示内皮细胞和上皮细胞中mRNA、蛋白质和功能的转录依赖性降低。ENT 1启动子的检查确定了缺氧诱导因子1（HIF-1）依赖性抑制ENT 1在缺氧。使用体外和体内模型的Ado信号，我们发现，减少Ado摄取促进血管屏障和抑制中性粒细胞组织积累在缺氧。此外，上皮Hif 1 α突变动物显示上皮ENT 1表达增加。总之，这些结果确定ENT的转录抑制作为缺氧期间升高细胞外Ado的先天机制。
Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1 α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.