PMID- 12370277
OWN - NLM
STAT- MEDLINE
DCOM- 20021104
LR  - 20220309
IS  - 0021-9738 (Print)
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Linking)
VI  - 110
IP  - 7
DP  - 2002 Oct
TI  - Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates 
      permeability changes in intestinal epithelia.
PG  - 993-1002
AB  - Under conditions of limited oxygen availability (hypoxia), multiple cell types 
      release adenine nucleotides in the form of ATP, ADP, and AMP. Extracellular AMP 
      is metabolized to adenosine by surface-expressed ecto-5'-nucleotidase (CD73) and 
      subsequently activates surface adenosine receptors regulating endothelial and 
      epithelial barrier function. Therefore, we hypothesized that hypoxia 
      transcriptionally regulates CD73 expression. Microarray RNA analysis revealed an 
      increase in CD73 and ecto-apyrase CD39 in hypoxic epithelial cells. Metabolic 
      studies of CD39/CD73 function in intact epithelia revealed that hypoxia enhances 
      CD39/CD73 function as much as 6 +/- 0.5-fold over normoxia. Examination of the 
      CD73 gene promoter identified at least one binding site for hypoxia-inducible 
      factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense 
      oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 
      expression. Studies using luciferase reporter constructs revealed a significant 
      increase in activity in cells subjected to hypoxia, which was lost in truncated 
      constructs lacking the HIF-1 site. Mutagenesis of the HIF-1alpha binding site 
      resulted in a nearly complete loss of hypoxia-inducibility. In vivo studies in a 
      murine hypoxia model revealed that hypoxia-induced CD73 may serve to protect the 
      epithelial barrier, since the CD73 inhibitor alpha,beta-methylene ADP promotes 
      increased intestinal permeability. These results identify an HIF-1-dependent 
      regulatory pathway for CD73 and indicate the likelihood that CD39/CD73 protects 
      the epithelial barrier during hypoxia.
FAU - Synnestvedt, Kristin
AU  - Synnestvedt K
AD  - Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
FAU - Furuta, Glenn T
AU  - Furuta GT
FAU - Comerford, Katrina M
AU  - Comerford KM
FAU - Louis, Nancy
AU  - Louis N
FAU - Karhausen, Jorn
AU  - Karhausen J
FAU - Eltzschig, Holger K
AU  - Eltzschig HK
FAU - Hansen, Karl R
AU  - Hansen KR
FAU - Thompson, Linda F
AU  - Thompson LF
FAU - Colgan, Sean P
AU  - Colgan SP
LA  - eng
GR  - HL-60569/HL/NHLBI NIH HHS/United States
GR  - R01 AI018220/AI/NIAID NIH HHS/United States
GR  - R01 HL060569/HL/NHLBI NIH HHS/United States
GR  - R01 DK050189/DK/NIDDK NIH HHS/United States
GR  - P01 DE013499/DE/NIDCR NIH HHS/United States
GR  - DK-50189/DK/NIDDK NIH HHS/United States
GR  - R29 DK050189/DK/NIDDK NIH HHS/United States
GR  - DE-13499/DE/NIDCR NIH HHS/United States
GR  - R37 DK050189/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Antigens, CD)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - EC 3.1.3.5 (5'-Nucleotidase)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 3.6.1.5 (Apyrase)
RN  - EC 3.6.1.5 (CD39 antigen)
SB  - IM
MH  - 5'-Nucleotidase/biosynthesis/*genetics
MH  - Adenosine Triphosphatases/biosynthesis
MH  - Antigens, CD/biosynthesis
MH  - Apyrase
MH  - Cell Hypoxia
MH  - Cells, Cultured
MH  - Cyclic AMP Response Element-Binding Protein/physiology
MH  - DNA-Binding Proteins/*physiology
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Intestinal Mucosa/*metabolism
MH  - Nuclear Proteins/*physiology
MH  - Permeability
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/analysis
MH  - *Transcription Factors
PMC - PMC151145
EDAT- 2002/10/09 04:00
MHDA- 2002/11/26 04:00
PMCR- 2002/10/01
CRDT- 2002/10/09 04:00
PHST- 2002/10/09 04:00 [pubmed]
PHST- 2002/11/26 04:00 [medline]
PHST- 2002/10/09 04:00 [entrez]
PHST- 2002/10/01 00:00 [pmc-release]
AID - 15337 [pii]
AID - 10.1172/JCI15337 [doi]
PST - ppublish
SO  - J Clin Invest. 2002 Oct;110(7):993-1002. doi: 10.1172/JCI15337.