期刊
BLOOD
卷 113, 期 1, 页码 224-232出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-06-165746
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资金
- National Institutes of Health [DK50189, HL60569, HL076540]
- Foundation for Anesthesia Education and Research
- German Research Foundation (Deutsche Forschungsgemeinschaft [DFG] [El274/4-1]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL076540, R01HL060569] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK050189, R29DK050189, R37DK050189] Funding Source: NIH RePORTER
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)
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