TY - JOUR
T1 - Prematurely senescent ARPE-19 cells display features of age-related macular degeneration
AU - Glotin, Anne Lise
AU - Debacq-Chainiaux, Florence
AU - Brossas, Jean Yves
AU - Faussat, Anne Marie
AU - Tréton, Jacques
AU - Zubielewicz, Anna
AU - Toussaint, Olivier
AU - Mascarelli, Frédéric
N1 - Publication code : RES. ACAD.
PY - 2008/4/1
Y1 - 2008/4/1
N2 - The etiology of age-related macular degeneration (AMD), the leading cause of blindness in the developed world, remains poorly understood, but may be related to cumulative oxidative stress. The prime target of the disease is the retinal pigmented epithelium (RPE). To study the molecular mechanisms underlying RPE degeneration, we investigated whether repetitive oxidative stress induced premature senescence in RPE cells from the human ARPE-19 cell line. After exposure to 8 mM tert-butylhydroperoxide (tert-BHP) for 1 h daily for 5 days, the cells showed four well-known senescence biomarkers: hypertrophy, senescence-associated β-galactosidase activity, growth arrest, and cell cycle arrest in G1. A specific low-density array followed by qRT-PCR validation allowed us to identify 36 senescence-associated genes differentially expressed in the prematurely senescent cells. Functional analysis demonstrated that premature senescence induced amyloid β secretion, resistance to acute stress by tert-BHP and amyloid β, and defects in adhesion and transepithelial permeability. Coculture assays with choroidal endothelial cells showed the proangiogenic properties of the senescent RPE cells. These results demonstrate that chronic oxidative stress induces premature senescence in RPE cells that modifies the transcriptome and substantially alters cell processes involved in the pathophysiology of AMD. Oxidative stress-induced premature senescence may represent an in vitro model for screening therapeutics against AMD and other retinal degeneration disorders. © 2007 Elsevier Inc. All rights reserved.
AB - The etiology of age-related macular degeneration (AMD), the leading cause of blindness in the developed world, remains poorly understood, but may be related to cumulative oxidative stress. The prime target of the disease is the retinal pigmented epithelium (RPE). To study the molecular mechanisms underlying RPE degeneration, we investigated whether repetitive oxidative stress induced premature senescence in RPE cells from the human ARPE-19 cell line. After exposure to 8 mM tert-butylhydroperoxide (tert-BHP) for 1 h daily for 5 days, the cells showed four well-known senescence biomarkers: hypertrophy, senescence-associated β-galactosidase activity, growth arrest, and cell cycle arrest in G1. A specific low-density array followed by qRT-PCR validation allowed us to identify 36 senescence-associated genes differentially expressed in the prematurely senescent cells. Functional analysis demonstrated that premature senescence induced amyloid β secretion, resistance to acute stress by tert-BHP and amyloid β, and defects in adhesion and transepithelial permeability. Coculture assays with choroidal endothelial cells showed the proangiogenic properties of the senescent RPE cells. These results demonstrate that chronic oxidative stress induces premature senescence in RPE cells that modifies the transcriptome and substantially alters cell processes involved in the pathophysiology of AMD. Oxidative stress-induced premature senescence may represent an in vitro model for screening therapeutics against AMD and other retinal degeneration disorders. © 2007 Elsevier Inc. All rights reserved.
KW - Aging
KW - Amyloid β
KW - Angiogenesis
KW - Free radicals
KW - Retina
KW - Tight junction
KW - Transcriptome
UR - http://www.scopus.com/inward/record.url?scp=40949121097&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2007.12.023
DO - 10.1016/j.freeradbiomed.2007.12.023
M3 - Article
C2 - 18226607
SN - 0891-5849
VL - 44
SP - 1348
EP - 1361
JO - Free Radical biology & medecine
JF - Free Radical biology & medecine
IS - 7
ER -