Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α.
The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration (AMD), the major cause of blinding in the elderly. In the present study, sulindac, a nonsteroidal antiinflammatory drug (NSAID), was tested for protection against oxidative stress-induced damage in an established RPE cell line (ARPE-19). Besides its established antiinflammatory activity, sulindac has previously been shown to protect cardiac tissue against ischemia/reperfusion damage, although the exact mechanism was not elucidated. As shown here, sulindac can also protect RPE cells from chemical oxidative damage or UV light by initiating a protective mechanism similar to what is observed in ischemic preconditioning (IPC) response. The mechanism of protection appears to be triggered by reactive oxygen species (ROS) and involves known IPC signaling components such as PKG and PKC epsilon in addition to the mitochondrial ATP-sensitive K(+) channel. Sulindac induced iNOS and Hsp70, late-phase IPC markers in the RPE cells. A unique feature of the sulindac protective response is that it involves activation of the peroxisome proliferator-activated receptor alpha (PPAR-α). We have also used low-passage human fetal RPE and polarized primary fetal RPE cells to validate the basic observation that sulindac can protect retinal cells against oxidative stress. These findings indicate a mechanism for preventing oxidative stress in RPE cells and suggest that sulindac could be used therapeutically for slowing the progression of AMD.
Graduate Program in Integrative Biology, Department of Biological Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL 33431;
Arunodoy
A
Sur
Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, FL 33458;
Shailaja
S
Kesaraju
Graduate Program in Integrative Biology, Department of Biological Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL 33431; Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, FL 33458; Center for Complex Systems and Brain Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL 33431; Department of Biomedical Sciences, College of Medicine, Florida Atlantic University, Boca Raton, FL 33431; and.
Howard
H
Prentice
Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, FL 33458;
Kasirajan
K
Ayyanathan
Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, FL 33458;
Diane
D
Baronas-Lowell
Department of Pathology and Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089.
Danhong
D
Zhu
Department of Pathology and Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089.
David R
DR
Hinton
Graduate Program in Integrative Biology, Department of Biological Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL 33431; Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, FL 33458; Center for Complex Systems and Brain Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL 33431;
Janet
J
Blanks
Center for Molecular Biology and Biotechnology, Florida Atlantic University, Jupiter, FL 33458; hweissba@fau.edu.
Herbert
H
Weissbach
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000502:physiology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects*; D013467:Sulindac / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D047493:PPAR alpha; D013467:Sulindac
age-related macular degeneration; oxidative stress; preconditioning; retinal pigmented epithelial cells; sulindac