May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
Aspirin and COX–2 inhibition reduce diabetic endothelial cell death via a Fas–FasL dependent mechanism.
Author Affiliations & Notes
  • A.M. Joussen
    Center Ophthalmology, Dept Vitreoretinal Surgery, Koln, Germany
  • V. Poulaki
    Retina Research Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 325 Cambridge Street, Boston, MA
  • S. Fauser
    Center Ophthalmology, Dept Vitreoretinal Surgery, Koln, Germany
  • N. Kociok
    Center Ophthalmology, Dept Vitreoretinal Surgery, Koln, Germany
  • N. Mitsiades
    Department of Adult Oncology,, Dana–Farber Cancer Institute, Harvard Medical School,, Boston, MA
  • Footnotes
    Commercial Relationships  A.M. Joussen, None; V. Poulaki, None; S. Fauser, None; N. Kociok, None; N. Mitsiades, None.
  • Footnotes
    Support  DFG Jo 324 /6–1, DFG Jo 324 / 4–1, DFG Ki 734 2–1, FFB
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 1095. doi:
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      A.M. Joussen, V. Poulaki, S. Fauser, N. Kociok, N. Mitsiades; Aspirin and COX–2 inhibition reduce diabetic endothelial cell death via a Fas–FasL dependent mechanism. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1095.

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

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Abstract

Abstract: : Purpose: Leukocyte adhesion to the diabetic retinal vasculature results in early blood–retinal barrier breakdown, capillary non–perfusion, and endothelial cell injury and death. We have previously demonstrated that aspirin administration or COX–2 inhibition reduces leukocyte adhesion in the diabetic retinal vasculature and suppressed blood–retinal barrier breakdown. In the current study we investigated the effect of aspirin administration and COX–2 inhibition on diabetes–induced leukocyte–mediated endothelial cell damage. Methods: STZ–induced diabetic animals were treated with daily intraperitoneal injections of 50mg/kg aspirin or 2mg/kg of the COX–2 inhibitor meloxicam. A subgroup of animals was treated with a neutralizing anti–FasL antibody or isotype–matched control (1mg/kg). Another subgroup was treated with the NF–kB inhibitor SN50. Leukocyte surface expression of FasL was analyzed by a modified immunoprecipitation protocol. Retinal endothelial apoptosis of diabetic rats was evaluated by TUNEL and DNA fragmentation ELISA. Leukocyte activities of NF–kB and p38MAPK were measured with a commercially available ELISA method. Results: In vivo treatment with aspirin or COX–2 inhibitors suppressed diabetes–induced p38MAPK and NF–kB activation, and FasL upregulation in leukocytes and subsequently the retinal endothelial cell apoptosis. Co–administration of an anti–FasL antibody with the aspirin or meloxicam treatment did not reduce endothelial cell apoptosis further, providing evidence that the observed effect of aspirin and COX–2 inhibition is through the Fas–FasL apoptotic pathway. Administration of the NF–kB inhibitor SN50 reduced FasL expression of the leukocytes and apoptotic cell death whereas co–administration of aspirin and meloxicam reduced apoptotic cell death even further, suggesting that aspirin and COX–2 inhibitors have other targers apart from NF–kB. Conclusions: Our studies demonstrate that aspirin and COX–2 inhibition prevent leukocyte–mediated endothelial apoptosis in diabetes through a Fas/FasL–dependent mechanism. Aspirin and COX–2 inhibition reduce FasL leukocyte expression through a mechanism partially dependent on the p38–induced NF–kB activation. Our study demonstrates that these pharmacological agents have a beneficial effect in early diabetic retinopathy.

Keywords: diabetic retinopathy • inflammation • cell death/apoptosis 
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