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Mizuki Tagami, Anna Janiak, Sotirios Tsimikas, Joseph L. Witztum, James T. Handa; Lipoprotein(a) Protects against Oxidized Phospholipid in the Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4298.
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Oxidative stress has been hypothesized to contribute to Age-related macular degeneration (AMD). Oxidized phosphatidylcholine (OxPL), results from chronic oxidative stimulation that occurs in AMD. In human plasma, OxPL is specifically bound by lipoprotein(a) (Lp(a)). We previously demonstrated the accumulation of oxidized apolipoprotein B100 lipoproteins (apoB) in drusen of AMD. Lp(a) is composed of apoB100, but it also contains the apo(a) protein. While Lp(a) is a risk factor for cardiovascular disease, its function in the retina is unknown. The purpose herein was to determine whether Lp(a) influences the phenotype of the retina.
Human AMD maculas were surveyed for Lp(a) and OxPL by IHC. Mice were fed a regular chow diet and exposed to a 12 hour on/off light cycle. Mice transgenic for human Lp(a) (containing both human apo(a) and human apoB100) and mice transgenic for a mutant Lp(a) unable to bind OxPL (muLp(a)- containing a human mutated apo(a) and human apoB100) were studied along with wild-type C57Bl6 and mice transgenic for human apoB were evaluated for OxPL using E06 antibody, and for AMD phenotype by electron microscopy (TEM).
Human AMD maculas (n=14) and age-matched controls (n=5) showed staining for Lp(a) and OxPL was confined to outer Bruch’s membrane and choroid. In AMD eyes, drusen stained for both Lp(a) and OxPL. While apo(a) was expressed in HepG2 cells, it was not expressed by human ARPE-19 cells using either RT-qPCR or Western blot analysis. We next compared the phenotype of Lp(a) to muLp(a) mice, which do not bind OxPL. Compared to muLp(a) mice, 12 mo Lp(a) mice had reduced OxPL in the retina, RPE, Bruch’s membrane, and choroid (n=8 per group). Semi-thin sections (n=10 per group) showed prominent intra-RPE vacuoles in 100% of muLp(a) and 10% of Lp(a) mice, and none in WT or ApoB mice. Drusen were seen in 30% of muLp(a) eyes only. TEM showed a marked increase in intracellular membranous vacuoles (p<0.006), basal laminar deposits (p=0.056), and outer collagenous layer deposits (p<0.003) in muLp(a) mice over all other groups.
Lp(a) localizes with oxPL to the outer macula. Our data support the hypothesis that Lp(a) removes OxPL from the posterior pole of retina, while impaired removal of oxPL -as in the muLp(a) mice- is associated with an early AMD phenotype.
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