Opposite effects of prostaglandin-J2 on VEGF in normoxia and hypoxia: role of HIF-1

• Published in: Biochemical and biophysical research communications Vol. 314; no. 1; pp. 31 - 38
• Main Authors: Józkowicz, Alicja, Nigisch, Anneliese, Wegrzyn, Joanna, Weigel, Guenter, Huk, Ihor, Dulak, Józef
• Format: Journal Article
• Language: English
• Published: United States 30-01-2004
• Subjects: Cell Hypoxia - physiology; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Membrane Proteins; Nuclear Proteins - metabolism; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - metabolism; Prostaglandin D2 - pharmacology; Reference Values; Transcription Factors; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0006-291X
• DOI: 10.1016/j.bbrc.2003.12.059

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.