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X. Fan, L. Reneker, S.M. Jarvis, M.E. Obrenovich, R. Cheng, B.J. Ortwerth, V.M. Monnier; Vitamin C Mediates Lens Crystallin Aging by Glycation in A Humanized Transgenic Mouse Model . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4738.
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© ARVO (1962-2015); The Authors (2016-present)
Human lens crystallins become progressively pigmented and crosslinked with age, in part due to glycation reactions by reactive carbonyl compounds. We hypothesized this process might be in part mediated by ascorbic acid oxidation products. However, unequivocal demonstration of this concept has not been possible due to the similarity of advanced glycation products (AGEs) from reducing sugars and oxidized vitamin C compounds.
Taking advantage from the fact that mice have very low lenticular levels of vitamin C, we created a humanized transgenic mouse lens expressing high levels of the human sodium dependent vitamin C transporter 2 (SVCT2) under control of the mouse alpha–crystallin promoter fused to the chicken lens delta1 crystallin enhancer (ΔenαA).
Analysis of the founder, F1 and F2 mice revealed sustained lenticular expression of SVCT2, with a 10–20 fold elevation of ascorbic acid (ASA) (1–3 mM) and dehydroascorbic acid (DHA) (0.05– 0.3 mM) levels in the lenses of the transgenic mice as compared to the wild–type mice, without impairment of GSH homeostasis in the transgenic lenses. At 6 and 10 months, the ASA–derived glycation products pentosidine and fluorescent K2P crosslinks were several fold highly increased compared to wild–type (p<0.0001), and significantly increased with age (p<0.001), while the glucose–derived Amadori product was normal. The digested lens protein fluorescence at ex/em 370/440 and 335/385 were also elevated in transgenic mice at both 6 and 10 month, and significantly higher at 10 month. Both fluorescence and glycation markers, i.e pentosidine and the fluorescent crosslink K2P level correlated with the lenticular ascorbic acid level.
Longitudinal studies are being carried out to evaluate the long–term impact of accelerated ascorbylation on the crystallin structure and the effect of pharmacological intervention of the process. This study provides the first unequivocal evidence for the participation of vitamin C degradation products in the chemical aging process of the lens.
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