Opposite effects of prostaglandin-J2 on VEGF in normoxia and hypoxia: role of HIF-1.
The vascular endothelial growth factor (VEGF) is produced in response to hypoxia or inflammatory cytokines. In normoxia VEGF synthesis is upregulated by 15-deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)) via induction of heme oxygenase-1 (HO-1). Here we compared the influence of 15d-PGJ(2) on VEGF expression in human microvascular endothelial cells in normoxia (approximately 20% O(2)) and hypoxia ( approximately 2% O(2)). Regardless of the oxygen concentration, 15d-PGJ(2) inhibited activity of hypoxia inducible factor-1 (HIF-1), the major hypoxic regulator of VEGF. However, in normoxic conditions 15d-PGJ(2) (1-10microM) activated the VEGF promoter and increased synthesis of the VEGF protein. Concomitantly, it strongly induced expression of HO-1. In contrast, in hypoxia, 15d-PGJ(2) decreased VEGF promoter activity and reduced VEGF release by 50%. Inhibition of HO-1 activity additionally attenuated VEGF synthesis in hypoxia. We conclude that induction of HO-1 by 15d-PGJ(2) results in augmentation of VEGF synthesis in normoxia. In hypoxia, however, the stimulatory effect of HO-1 is outweighed by 15d-PGJ(2)-mediated inhibition of the HIF-1 pathway.
Józkowicz
Alicja
A
Department of Molecular Genetics, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland. alicia@mol.uj.edu.pl
Nigisch
Anneliese
A
Wegrzyn
Joanna
J
Weigel
Guenter
G
Huk
Ihor
I
Dulak
Józef
J
D015687:Cell Hypoxia / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D012016:Reference Values; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C477819:15-deoxyprostaglandin J2; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D015230:Prostaglandin D2