Central role of Sp1-regulated CD39 in hypoxia/ischemia protection
Central role of Sp1-regulated CD39 in hypoxia/ischemia protection
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DOI：
10.1182/blood-2008-06-165746
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发表时间：
2009-01-01
期刊：
影响因子：
20.3
通讯作者：
Colgan, Sean P.
中科院分区：
文献类型：
--
作者：
Eltzschig, Holger K.;Koehler, David;Colgan, Sean P.
缺氧是常见的几种炎症性疾病，其中多种细胞类型释放腺嘌呤核苷酸（特别是腺苷三磷酸/腺苷二磷酸）。三磷酸腺苷/二磷酸腺苷通过由CD 39（外核苷-三磷酸-二磷酸水解酶-1）启动的2步酶促反应代谢为腺苷。因此，细胞外腺苷可用于调节多种炎症终点。在这里，我们假设缺氧转录上调CD 39的表达。初步研究显示，CD 39 mRNA和内皮细胞免疫反应性的缺氧依赖性增加。对人CD 39基因启动子的检查鉴定了在缺氧诱导中重要的区域。多层次的分析，包括定点诱变，染色质免疫沉淀，和反义抑制，揭示了转录因子Sp1在缺氧诱导的CD 39的关键作用。在体内心肌缺血模型中使用cd 39（-/-）小鼠和Sp1小干扰RNA的组合揭示了心肌缺血期间Sp1介导的心脏CD 39的诱导。总之，这些结果确定了一种新的Sp1依赖性调节途径的CD 39和表明的可能性，CD 39是中央的保护性反应缺氧/缺血。（血。2009; 113：224-232）
Hypoxia is common to several inflammatory diseases, where multiple cell types release adenine-nucleotides (particularly adenosine triphosphate/adenosine diphosphate). Adenosine triphosphate/adenosine diphosphate is metabolized to adenosine through a 2-step enzymatic reaction initiated by CD39(ectonucleoside-triphosphate-diphosphohydrolase-1). Thus, extracellular adenosine becomes available to regulate multiple inflammatory endpoints. Here, we hypothesized that hypoxia transcriptionally up-regulates CD39 expression. Initial studies revealed hypoxia-dependent increases in CD39 mRNA and immunoreactivity on endothelia. Examination of the human CD39 gene promoter identified a region important in hypoxia inducibility. Multiple levels of analysis, including site-directed mutagenesis, chromatin immunoprecipitation, and inhibition by antisense, revealed a critical role for transcription-factor Sp1 in hypoxia-induction of CD39. Using a combination of cd39(-/-) mice and Sp1 small interfering RNA in in vivo cardiac ischemia models revealed Sp1-mediated induction of cardiac CD39 during myocardial ischemia. In summary, these results identify a novel Sp1-dependent regulatory pathway for CD39 and indicate the likelihood that CD39 is central to protective responses to hypoxia/ischemia. (Blood. 2009; 113: 224-232)