Nipradilol and timolol induce Foxo3a and peroxiredoxin 2 expression and protect trabecular meshwork cells from oxidative stress.
OBJECTIVE
Oxidative stress plays an important role in pathogenesis of glaucoma. The purpose of this study is to investigate the novel effect of antiglaucoma drugs on the expression of antioxidant peroxiredoxins of trabecular meshwork (TM) cells.


METHODS
The expression of the peroxiredoxin family was investigated using immortalized TM cell lines. Cells were treated with antiglaucoma drugs and analyzed for the expression of peroxiredoxin, and cellular sensitivity to oxidative stress. Furthermore, the effect of antiglaucoma drugs on the molecular regulation of the expression of peroxiredoxin was examined using a reporter assay and siRNA strategy.


RESULTS
Glaucomatous TM cells highly express peroxiredoxin 2 when compared with normal TM cells. Nipradilol and timolol, but not latanoprost, induce the expression of peroxiredoxin 2 through the activation of the Foxo3a transcription factor. TM cells showed reduced sensitivity to H(2)O(2) when cells were treated with either nipradilol or timolol, but not with latanoprost. In addition, both Foxo3a and PRDX2 expression were enhanced by drug-induced signal transduction through its receptor.


CONCLUSIONS
These results indicate that both nipradilol and timolol possess a novel mechanism of action and function as potent protective agents against oxidative stress.
Miyamoto
Naoya
N
Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
Izumi
Hiroto
H
Miyamoto
Rie
R
Kubota
Toshiaki
T
Tawara
Akihiko
A
Sasaguri
Yasuyuki
Y
Kohno
Kimitoshi
K
D000959:Antihypertensive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection; D004591:Electrophoresis, Polyacrylamide Gel; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D011412:Propanolamines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013999:Timolol / Q000494:pharmacology; D014129:Trabecular Meshwork / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000959:Antihypertensive Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011412:Propanolamines; D034741:RNA, Small Interfering; D013999:Timolol; D006861:Hydrogen Peroxide; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; C036089:nipradilol