May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
20-HETE Is a Nonhypoxic Regulator of HIF in Endothelial Cells
Author Affiliations & Notes
  • A. M. Guo
    Eye Care Services, Henry Ford Health System, Detroit, Michigan
  • P. A. Edwards
    Eye Care Services, Henry Ford Health System, Detroit, Michigan
  • J. C. Falck
    Biochemistry, University of Texas Southewestern Medical Center, Dallas, Texas
  • R. J. Roman
    Physiology, Medical College of Wisconsin, Milwaulkee, Wisconsin
  • A. G. Scicli
    Eye Care Services, Henry Ford Health System, Detroit, Michigan
  • Footnotes
    Commercial Relationships  A.M. Guo, None; P.A. Edwards, None; J.C. Falck, None; R.J. Roman, None; A.G. Scicli, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2652. doi:https://doi.org/
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      A. M. Guo, P. A. Edwards, J. C. Falck, R. J. Roman, A. G. Scicli; 20-HETE Is a Nonhypoxic Regulator of HIF in Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2652. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : We studied whether 20-HETE also leads to the activation of HIF-1α in EC.Methods and

Results: : We used the stable 20-HETE analog WIT003, and found that there was a marked increase in HIF-1α expression 6 hr after the addition of 10 µM WIT003. VEGF increases 4 hr after WIT003 thus preceding changes in HIF-1α. These changes in HIF-1α were suppressed by a VEGF neutralizing antibody and by the VEGF Receptor2 kinase inhibitor SU5416, suggesting that the increase in HIF-1α induced by WIT003 are mediated by VEGF. Incubation with PEG-SOD (400 U/ml), apocynin (100 µM) or DPI (10 µM) inhibited the increases in HIF-1α expression, thus indicating that NADPH oxidase-dependent superoxide is involved in mediating the response. Furthermore, WIT003 induced an increased p47phox expression in EC prior to the activation of HIF-1α, as well as translocation to the cell membrane indicating the assembly and activation of the NADPH subunits. WIT003-induced HIF-1α is dependent on MAPK activation since incubation with the MEK1/ERK1/2 inhibitor U0126 completely abolishes the increases in both VEGF and HIF-1α. Since the erithropoietin receptor is downstream of HIF, we tested whether this protein was altered after treatment with WIT003. We found that EpoR doubled after WIT003 treatment.

Conclusions: : These results suggest that 20-HETE may be a novel non-hypoxic regulator of HIF-1α, and thus HIF-dependent genes in EC.

Keywords: hypoxia • vascular endothelial growth factor • lipids 
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