HIF-dependent induction of adenosine A2B receptor in hypoxia
HIF-dependent induction of adenosine A2B receptor in hypoxia
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DOI：
10.1096/fj.06-6419com
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
Colgan, Sean P.
中科院分区：
文献类型：
--
作者：
Kong, Tianqing;Westerman, Karen A.;Colgan, Sean P.
腺苷与多种原因的缺氧广泛相关，包括与炎症和肿瘤发生有关的缺氧。最近的一些研究表明，在组织缺氧的地方，代谢控制腺苷的产生。在这里，我们通过内皮和上皮腺苷受体的转录调节来研究腺苷受体的控制和信号的放大。初步研究证实了先前的发现，即缺氧可选择性诱导人腺苷A2B受体（A2BR）。对克隆的人A2BR启动子进行分析，发现A2BR启动子中存在一个功能性缺氧响应区，包括缺氧诱导因子（HIF）的功能结合位点。进一步的研究检测了HIF-1 α的DNA结合和HIF-1 α功能的获得和丧失，证实了HIF-1 α在体外和体内小鼠模型中对A2BR诱导的强烈依赖性。内皮细胞过表达全长A2BR的进一步研究显示屏障功能增强和血管生成增强的功能表型。综上所述，这些结果证明了缺氧时HIF-1 α和腺苷信号放大对A2BR的转录协调作用。这些发现可能提供了缺氧与炎症和血管生成相关的代谢条件之间的重要联系。
Adenosine has been widely associated with hypoxia of many origins, including those associated with inflammation and tumorogenesis. A number of recent studies have implicated metabolic control of adenosine generation at sites of tissue hypoxia. Here, we examine adenosine receptor control and amplification of signaling through transcriptional regulation of endothelial and epithelial adenosine receptors. Initial studies confirmed previous findings indicating selective induction of human adenosine A2B receptor (A2BR) by hypoxia. Analysis of the cloned human A2BR promoter identified a functional hypoxia-responsive region, including a functional binding site for hypoxia-inducible factor (HIF) within the A2BR promoter. Further studies examining HIF-1 alpha DNA binding and HIF-1 alpha gain and loss of function confirmed strong dependence of A2BR induction by HIF-1 alpha in vitro and in vivo mouse models. Additional studies in endothelia overexpressing full-length A2BR revealed functional phenotypes of increased barrier function and enhanced angiogenesis. Taken together, these results demonstrate transcriptional coordination of A2BR by HIF-1 alpha and amplified adenosine signaling during hypoxia. These findings may provide an important link between hypoxia and metabolic conditions associated with inflammation and angiogenesis.