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(Investigative Ophthalmology and Visual Science. 2003;44:4163-4170.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0655
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Coordinate Activation of HIF-1 and NF-{kappa}B DNA Binding and COX-2 and VEGF Expression in Retinal Cells by Hypoxia

Walter J. Lukiw,1,2 Anna Ottlecz,3 George Lambrou,3 Monika Grueninger,3 Joelle Finley,1 Hilary W. Thompson,1,2 and Nicolas G. Bazan1,2

1From the Neuroscience Center and 2Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and the 3Novartis Institute for Biomedical Research, Basel, Switzerland.

PURPOSE. Proinflammatory signaling mechanisms are implicated in the induction of retinal neovascularization (NV) during ischemic retinopathies. This study examined transcription factor (TF) AP-1, HIF-1, and NF-{kappa}B DNA-binding in relation to cyclooxygenase (COX)-2 and VEGF RNA and protein levels in hypoxia-triggered monkey choroidal retinal (RF/6A) endothelial cells. Effects of the carboxamide CGP43182 were tested on COX-2 and VEGF activation and prostaglandin (PG)E2 release.

METHODS. RF/6A cells were subjected to hypoxia for 1 and 3 hours, at which times RNA and proteins were isolated. Potential AP-1, hypoxia-inducible factor (HIF)-1 and NF-{kappa}B DNA-binding sites were identified using DNA sequence search algorithms and were analyzed using gel-shift assay. COX-2 and VEGF RNA, protein, and PGE2 levels were quantified by RT-PCR, Western analysis, and enzyme immunoassay, respectively. Tubular morphogenesis was analyzed with phase-contrast imaging microscopy.

RESULTS. Nuclear AP-1, HIF-1 and NF-{kappa}B promoter DNA binding increased 1.5-, 4-, and 3-fold, respectively, after 1 hour of hypoxia. COX-2 RNA was elevated five- and fourfold after 1 and 3 hours of hypoxia, respectively. VEGF RNA and protein abundance lagged behind COX-2 induction but were each increased two- to threefold 3 hours after hypoxia. CGP43182 was found to inhibit NF-{kappa}B DNA binding, COX-2 and VEGF gene expression, PGE2 release, and hypoxia-induced tubular morphogenesis.

CONCLUSIONS. Maximum HIF-1 and NF-{kappa}B DNA binding immediately before COX-2 expression suggests that these TFs are important regulators of COX-2 induction in hypoxic RF/6A cells. IL-1ß emulated AP-1, HIF-1, and NF-{kappa}B DNA binding during hypoxia and may be a novel cytokine trigger for NV. CGP43182 appears to be an effective inhibitor of NV. VEGF expression appears to be regulated through dual interdependent mechanisms involving HIF-1 directly and indirectly through NF-{kappa}B-mediated COX-2 expression and PGE2 production.




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