TY - JOUR
T1 - Overexpression of SOD in retina
T2 - Need for increase in H 2O 2-detoxifying enzyme in same cellular compartment
AU - Usui, Shinichi
AU - Oveson, Brian C.
AU - Iwase, Takeshi
AU - Lu, Lili
AU - Lee, Sun Young
AU - Jo, Young Joon
AU - Wu, Zhihao
AU - Choi, Eun Young
AU - Samulski, Richard J.
AU - Campochiaro, Peter A.
N1 - Funding Information:
This work was supported by R01 EY05951 (P.A.C.) and P01 AG01751 (R.J.S.) from the NIH and a gift from Dr. and Mrs. William Lake. Shinichi Usui is a Bausch and Lomb Japan Vitreoretinal Research Fellow and was supported by The Osaka Medical Research Foundation for Incurable Diseases. P.A.C. is the George S. and Dolores Dore Eccles Professor of Ophthalmology and Neuroscience.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - In retinitis pigmentosa (RP), various mutations cause rod photoreceptor cell death leading to increased oxygen levels in the outer retina, progressive oxidative damage to cones, and gradual loss of cone cell function. We have been exploring the potential of overexpressing components of the endogenous antioxidant defense system to preserve cone cell function in rd10 +/+ mice, a model of RP. rd10 +/+ mice deficient in superoxide dismutase 1 (SOD1) showed increased levels of superoxide radicals and carbonyl adducts (a marker of oxidative damage) in the retina and more rapid loss of cone function than rd10 +/+ mice with normal levels of SOD1. This suggests that SOD1 is an important component of the antioxidant defense system of cones, but increased expression of SOD1 in rd10 +/+ mice increased oxidative damage and accelerated the loss of cone function. Coexpression of SOD1 with glutathione peroxidase 4 (Gpx4), which like SOD1 is localized in the cytoplasm, but not with catalase targeted to the mitochondria, reduced oxidative damage in the retina and significantly slowed the loss of cone cell function in rd10 +/+ mice. Gene transfer resulting in increased expression of SOD2, but not coexpression of SOD2 and mitochondrial Gpx4, resulted in high levels of H 2O 2 in the retina. These data suggest that to provide benefit in RP, overexpression of an SOD must be combined with expression of a peroxide-detoxifying enzyme in the same cellular compartment.
AB - In retinitis pigmentosa (RP), various mutations cause rod photoreceptor cell death leading to increased oxygen levels in the outer retina, progressive oxidative damage to cones, and gradual loss of cone cell function. We have been exploring the potential of overexpressing components of the endogenous antioxidant defense system to preserve cone cell function in rd10 +/+ mice, a model of RP. rd10 +/+ mice deficient in superoxide dismutase 1 (SOD1) showed increased levels of superoxide radicals and carbonyl adducts (a marker of oxidative damage) in the retina and more rapid loss of cone function than rd10 +/+ mice with normal levels of SOD1. This suggests that SOD1 is an important component of the antioxidant defense system of cones, but increased expression of SOD1 in rd10 +/+ mice increased oxidative damage and accelerated the loss of cone function. Coexpression of SOD1 with glutathione peroxidase 4 (Gpx4), which like SOD1 is localized in the cytoplasm, but not with catalase targeted to the mitochondria, reduced oxidative damage in the retina and significantly slowed the loss of cone cell function in rd10 +/+ mice. Gene transfer resulting in increased expression of SOD2, but not coexpression of SOD2 and mitochondrial Gpx4, resulted in high levels of H 2O 2 in the retina. These data suggest that to provide benefit in RP, overexpression of an SOD must be combined with expression of a peroxide-detoxifying enzyme in the same cellular compartment.
KW - Catalase
KW - Free radicals
KW - Glutathione peroxidase
KW - Photoreceptors
KW - Reactive oxygen species
KW - Retina
KW - Retinitis pigmentosa
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U2 - 10.1016/j.freeradbiomed.2011.06.010
DO - 10.1016/j.freeradbiomed.2011.06.010
M3 - Article
C2 - 21736939
AN - SCOPUS:80052262248
SN - 0891-5849
VL - 51
SP - 1347
EP - 1354
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 7
ER -