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PMID: 18812468 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Blood ·Vol. 113 ·No. 1 ·2009-01-01 ·Pages 224-32

Eltzschig HK, Köhler D, Eckle T, Kong T, Robson SC, Colgan SP

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.

MeSH Terms
Animals Antigens, CD/genetics,metabolism Apyrase/genetics,metabolism Cells, Cultured Disease Models, Animal Endothelial Cells/cytology,metabolism Female Gene Expression Regulation/physiology Humans Hypoxia/metabolism,pathology,physiopathology Male Mice Mice, Inbred C57BL Mutagenesis, Site-Directed Myocardial Infarction/metabolism,pathology,physiopathology Myocardial Reperfusion Injury/metabolism,pathology,physiopathology Promoter Regions, Genetic/physiology RNA, Messenger/metabolism RNA, Small Interfering Sp1 Transcription Factor/metabolism
Chemicals
Antigens, CD RNA, Messenger RNA, Small Interfering Sp1 Transcription Factor Apyrase CD39 antigen
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Eltzschig Holger K
Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver, CO, USA. [email protected]
Köhler David
Eckle Tobias
Kong Tianqing
Robson Simon C
Colgan Sean P
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2008-06-165746
Email
[email protected]
Published
2009-01-01
Epub
2008-00-23
Pages
224-32
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2614635
Subset
IM
Grants
NIDDK NIH HHS · DK 50189 · United States
NHLBI NIH HHS · R01 HL060569 · United States
NIDDK NIH HHS · R01 DK050189 · United States
NHLBI NIH HHS · HL 076540 · United States
NIDDK NIH HHS · R29 DK050189 · United States
NHLBI NIH HHS · HL 60569 · United States
NIDDK NIH HHS · R37 DK050189 · United States
NHLBI NIH HHS · P01 HL076540 · United States
External Links
PubMed source DOI: 10.1182/blood-2008-06-165746 PMC Full Text View journal details
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