Regulation of cell death and survival pathways in experimental glaucoma.
This study investigates cell death and survival pathways in experimental glaucoma using the translimbal photocoagulation laser model. Glaucoma was induced unilaterally in 79 Wistar rats and all eyes developed elevated intraocular pressure. The involvement of caspase-3, p-AKT and members of the MAP kinase pathway was evaluated by immunohistochemistry and Western blotting. We found that protein levels of caspase-3 were elevated from day 15 to day 30 (p<0.05). All investigated members of the MAP kinase pathway were significantly activated. P-SAPK/JNK activation began on day 2, reaching a 6-fold elevation by day 30 (p<0.05). The p-P38 level was elevated on days 2 and 8 (p<0.05), followed by a decrease to baseline on day 15. The level of p-ATF-2, the substrate of P38, was significantly elevated at all time points tested, up to day 30 (p<0.05). P-ERK was detected early (p<0.05) on day 1, returning to normal on day 15. The pro-survival protein p-Akt, a member of the PI3-kinase survival pathway, was also detected early on day 1 (p<0.05) returning to baseline on day 8 and remaining unchanged up to 64days. We conclude that retinal ganglion cell death in glaucoma involves activation, at different time points, of multiple pro-apoptotic pathways (the MAP kinase pathway and the caspase family) and pro-survival (PI-3 Kinase/ Akt and p-ERK).
Levkovitch-Verbin
Hani
H
Sam Rothberg Ophthalmic Molecular Biology Laboratory, Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer 52621, Israel. halevko@hotmail.com
Harizman
Noga
N
Dardik
Rima
R
Nisgav
Yael
Y
Vander
Shelly
S
Melamed
Shlomo
S
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005901:Glaucoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007429:Intraocular Pressure; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3