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Blood, 1 January 2009, Vol. 113, No. 1, pp. 224-232. Prepublished online as a Blood First Edition Paper on September 23, 2008; DOI 10.1182/blood-2008-06-165746. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-06-165746v1 113/1/224    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Eltzschig, H. K. Articles by Colgan, S. P. Search for Related Content PubMed PubMed Citation Articles by Eltzschig, H. K. Articles by Colgan, S. P. Related Collections Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Central role of Sp1-regulated CD39 in hypoxia/ischemia protection Holger K. Eltzschig13, David Köhler2, Tobias Eckle13, Tianqing Kong4, Simon C. Robson5, and Sean P. Colgan3 1 Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver; 2 Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany; 3 Mucosal Inflammation Program, Department of Medicine, University of Colorado Health Sciences Center, Denver; 4 Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and 5 Gastroenterology Division, Department of Medicine, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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