Central role of Sp1-regulated CD39 in hypoxia/ischemia protection

Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.
Blood (Impact Factor: 10.43). 10/2008; 113(1):224-32. DOI: 10.1182/blood-2008-06-165746
Source: PubMed

ABSTRACT 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.

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    • "Inhibition of HIF-1α by antisense oligonucleotides or point mutations in the hypoxia response element of the CD73 promoter has been reported to inhibit hypoxia-induced CD73 expression [22] [23] [24]. Notably, hypoxia also upregulates CD39, A2A, and A2B adenosine receptor expression [25] [26]. Another pathway that can induce CD73 expression is the Wnt pathway. "
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    • "Both CD39 and CD73 expressions are dynamic and change under pathophysiological conditions. Hypoxia upregulates both ectoenzymes—CD39 through Sp1- dependent pathways [4] and CD73 through binding of HIF- 1 [5]. Further, within the CD73 gene, promoter region is a cAMP response element (CRE) which regulates transcription through cAMP-dependent CRE-binding protein (CREB). "
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