title: Dietary antioxidants prevent age-related retinal pigment epithelium actin damage and blindness in mice lacking αvβ5 integrin.
abstract: 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 αvβ5 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 β5(-/-) 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 β5(-/-) 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.
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA.
authors.forename: Chia-Chia
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U968, Paris 75012, France; Institut de la Vision, Université Pierre et Marie Curie-Paris 06, UMR_S 968, Paris 75012, France; Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France.
authors.forename: Emeline F
authors.initials: EF
authors.lastname: Nandrot
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dun
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA. Electronic address: finnemann@fordham.edu.
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Finnemann
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis; D001766:Blindness / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D019587:Dietary Supplements; D004596:Electroretinography; D008062:Lipofuscin / Q000378:metabolism; D008268:Macular Degeneration / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D008517:Phytotherapy; D028321:Plant Preparations / Q000627:therapeutic use*; D050050:Protein Carbonylation / Q000187:drug effects; D055550:Protein Stability; D019030:Receptors, Vitronectin / Q000172:deficiency* / Q000235:genetics; D012160:Retina / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D027843:Vitis
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D008062:Lipofuscin; D028321:Plant Preparations; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C027576:4-hydroxy-2-nonenal