Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 36, Pages 13480-13484Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0601552103
Keywords
oxidation
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Funding
- NCI NIH HHS [R01 CA106415, CA106415] Funding Source: Medline
- NEI NIH HHS [EY06603, R01 EY006603, F32 EY006603, R01 EY014239, EY015638, EY014239, R24 EY015638, R01 EY016490, EY016490] Funding Source: Medline
- NIGMS NIH HHS [R01 GM021249, GM21249] Funding Source: Medline
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Choroidal neovascularization (CNV), the advanced stage of age-related macular degeneration (AMD), accounts for > 80% of vision loss in AMD. Carboxyethylpyrrole (CEP) protein modifications, uniquely generated from oxidation of docosahexaenoate-containing lipids, are more abundant in Bruch's membrane from AMD eyes. We tested the hypothesis that CEP protein adducts stimulate angiogenesis and possibly contribute to CNV in AMD. Human serum albumin (HSA) or acetyl-Gly-Lys-O-methyl ester (dipeptide) were chemically modified to yield CEP-modified HSA (CEP-HSA) or CEP-dipeptide. The in vivo angiogenic properties of CEP-HSA and CEP-dipeptide were demonstrated by using the chick chorioallantoic membrane and rat corneal micropocket assays. Low picomole amounts of CEP-HSA and CEP-dipeptide stimulated neovascularization. Monoclonal anti-CEP antibody neutralized limbal vessel growth stimulated by CEP-HSA, whereas anti-VEGF antibody was found to only partially neutralize vessel growth. Subretinal injections of CEP-modified mouse serum albumin exacerbated laser-induced CNV in mice. In vitro treatments of human retinal pigment epithelial cells with CEP-dipeptide or CEP-HSA did not induce increased VEGF secretion. Overall, these results suggest that CEP-induced angiogenesis utilizes VEGF-independent pathways and that anti-CEP therapeutic modalities might be of value in limiting CNV in AMD.
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