PMID- 14702352
OWN - NLM
STAT- MEDLINE
DCOM- 20040507
LR  - 20220311
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 13
DP  - 2004 Mar 26
TI  - Hypoxic regulation of angiopoietin-2 expression in endothelial cells.
PG  - 12171-80
AB  - Exposure of endothelial cells to hypoxia-induced angiopoietin-2 (Ang2) 
      expression. The increase in Ang2 mRNA levels occurred by transcriptional 
      regulation and by post-transcriptional increase in mRNA stability. Induction of 
      Ang2 mRNA resulted in an increase of intracellular and secreted Ang2 protein 
      levels. Since the transcriptional regulation of several genes involved in 
      angiogenesis during hypoxia is mediated by hypoxia-inducible factor-1 (HIF-1), it 
      was conceivable that Ang2 expression might be regulated by the same 
      oxygen-dependent mechanism. However, our data showed that pharmacological HIF 
      inducers, CoCl(2) and DFO, did not affect Ang2 expression. Moreover, 
      HIF-1-deficient hepatoma cell (Hepa1 c4) and its wild-type counterpart (Hepa1 
      c1c4) up-regulates Ang2 during hypoxia. These results indicated that 
      hypoxia-driven Ang2 expression may be independent of the HIF pathway. Using 
      neutralizing VEGF antibody or pharmacological inhibitors of VEGF receptors, we 
      showed that hypoxia-induced VEGF participates but could not account completely 
      for Ang2 expression during hypoxia. In addition, hypoxia elicited an increase of 
      cyclooxygenase-2 (COX-2) expression and a parallel increase in prostanglandin 
      E(2) (PGE(2)) and prostacyclin (PGI(2)) production. COX-2 inhibitors decreased 
      the hypoxic induction of Ang2 and the hypoxic induction of PGE(2) and PGI(2) in a 
      dose-dependent manner. Similarly, COX-2 but not COX-1 antisense treatment 
      decreased hypoxic induction of Ang2 expression, and this effect was reversed by 
      exogenous PGE(2). Finally, exogenous PGE(2) and PGI(2) were able to stimulate 
      Ang2 under normoxic conditions. These findings suggest that COX-2-dependent 
      prostanoids may play an important role in the regulation of hypoxia-induced Ang2 
      expression.
FAU - Pichiule, Paola
AU  - Pichiule P
AD  - Department of Anatomy, Case Western Reserve University, School of Medicine, 10900 
      Euclid Avenue, Cleveland, OH 44106, USA.
FAU - Chavez, Juan C
AU  - Chavez JC
FAU - LaManna, Joseph C
AU  - LaManna JC
LA  - eng
GR  - NS 37111/NS/NINDS NIH HHS/United States
GR  - NS 38632/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20031230
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Angiopoietin-2)
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (DNA, Complementary)
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 (Iron Chelating Agents)
RN  - 0 (Isoenzymes)
RN  - 0 (Lactones)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (Prostaglandins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Sulfones)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0QTW8Z7MCR (rofecoxib)
RN  - 3G0H8C9362 (Cobalt)
RN  - DCR9Z582X0 (Epoprostenol)
RN  - EC 1.14.99.1 (Cyclooxygenase 1)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.14.99.1 (PTGS1 protein, human)
RN  - EC 1.14.99.1 (PTGS2 protein, human)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
RN  - EVS87XF13W (cobaltous chloride)
RN  - J06Y7MXW4D (Deferoxamine)
RN  - K7Q1JQR04M (Dinoprostone)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Angiopoietin-2/*biosynthesis
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Nucleus/metabolism
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Cobalt/pharmacology
MH  - Cyclooxygenase 1
MH  - Cyclooxygenase 2
MH  - Cyclooxygenase 2 Inhibitors
MH  - Cyclooxygenase Inhibitors/pharmacology
MH  - DNA, Complementary/metabolism
MH  - DNA-Binding Proteins/*metabolism
MH  - Deferoxamine/pharmacology
MH  - Dinoprostone/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Endothelium, Vascular/cytology/*enzymology/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Epoprostenol/metabolism
MH  - Humans
MH  - *Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Inhibitory Concentration 50
MH  - Iron Chelating Agents/pharmacology
MH  - Isoenzymes/biosynthesis
MH  - Lactones/pharmacology
MH  - Membrane Proteins
MH  - Nuclear Proteins/*metabolism
MH  - Oligonucleotides, Antisense/pharmacology
MH  - Oxygen/*metabolism
MH  - Prostaglandin-Endoperoxide Synthases/biosynthesis
MH  - Prostaglandins/metabolism
MH  - RNA, Messenger/metabolism
MH  - Recombinant Proteins/chemistry
MH  - Sulfones
MH  - Time Factors
MH  - *Transcription Factors
MH  - *Transcription, Genetic
MH  - Transcriptional Activation
MH  - Umbilical Veins/cytology
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/metabolism
EDAT- 2004/01/02 05:00
MHDA- 2004/05/08 05:00
CRDT- 2004/01/02 05:00
PHST- 2004/01/02 05:00 [pubmed]
PHST- 2004/05/08 05:00 [medline]
PHST- 2004/01/02 05:00 [entrez]
AID - S0021-9258(19)64150-5 [pii]
AID - 10.1074/jbc.M305146200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Mar 26;279(13):12171-80. doi: 10.1074/jbc.M305146200. Epub 2003 
      Dec 30.