Dietary antioxidants prevent age-related retinal pigment epithelium actin damage and blindness in mice lacking alpha v beta 5 integrin

作者：Yu Chia Chia; Nandrot Emeline F; Dun Ying; Finnemann Silvia C^*

来源：Free Radical Biology and Medicine, 2012, 52(3): 660-670.

DOI：10.1016/j.freeradbiomed.2011.11.021

• Actin
• Age-related blindness
• Antioxidant
• Cytoskeleton
• 4-Hydroxynonenal
• Lipotuscin
• Oxidative stress
• Protein oxidation
• Retina
• Retinal pigment epithelium
• Free radicals

In the aging human eye, oxidative damage and accumulation of pro-oxidant lysosomal lipofuscin cause functional decline of the retinal pigment epithelium (RPE), which contributes to age-related macular degeneration. In mice with an RPE-specific phagocytosis defect due to lack of alpha v beta 5 integrin receptors, RPE accumulation of lipofuscin suggests that the age-related blindness we previously described in this model may also result from oxidative stress. Cellular and molecular targets of oxidative stress in the eye remain poorly understood. Here we identify actin among 4-hydroxynonenal (HNE) adducts formed specifically in beta 5(-/-) RPE but not in neural retina with age. HNE modification directly correlated with loss of resistance of actin to detergent extraction, suggesting cytoskeletal damage in aging RPE. Dietary enrichment with natural antioxidants, grapes or marigold extract containing macular pigments lutein/zeaxanthin, was sufficient to prevent HNE-adduct formation, actin solubility, lipofuscin accumulation, and age-related cone and rod photoreceptor dysfunction in beta 5(-/-) mice. Acute generation of HNE adducts directly destabilized actin but not tubulin cytoskeletal elements of RPE cells. These findings identify destabilization of the actin cytoskeleton as a consequence of a physiological, sublethal oxidative burden of RPE cells in vivo that is associated with age-related blindness and that can be prevented by consuming an antioxidant-rich diet.

• 出版日期2012-2-1