Kong Tianqing, Westerman Karen A, Faigle Marion, Eltzschig Holger K, Colgan Sean P
Center for Experimental Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
FASEB J. 2006 Nov;20(13):2242-50. doi: 10.1096/fj.06-6419com.
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-1alpha DNA binding and HIF-1alpha gain and loss of function confirmed strong dependence of A2BR induction by HIF-1alpha 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-1alpha and amplified adenosine signaling during hypoxia. These findings may provide an important link between hypoxia and metabolic conditions associated with inflammation and angiogenesis.
腺苷与多种原因引起的缺氧广泛相关，包括与炎症和肿瘤发生相关的缺氧。最近的一些研究表明，在组织缺氧部位，腺苷生成存在代谢调控。在此，我们通过对内皮和上皮腺苷受体的转录调控来研究腺苷受体的控制及信号放大。初步研究证实了之前的发现，即缺氧可选择性诱导人腺苷A2B受体（A2BR）。对克隆的人A2BR启动子的分析确定了一个功能性缺氧反应区域，包括A2BR启动子内缺氧诱导因子（HIF）的一个功能性结合位点。进一步研究HIF-1α与DNA的结合以及HIF-1α功能的获得与丧失，证实了在体外和体内小鼠模型中，HIF-1α对A2BR诱导的强烈依赖性。对过表达全长A2BR的内皮细胞的进一步研究揭示了屏障功能增强和血管生成增加的功能表型。综上所述，这些结果表明HIF-1α对A2BR的转录协调作用以及缺氧期间腺苷信号的放大。这些发现可能为缺氧与炎症和血管生成相关的代谢状况之间提供重要联系。
