Carboxyethylpyrrole Oxidative Protein Modifications Stimulate Neovascularization: Implications for Age-Related Macular Degeneration

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 36; pp. 13480 - 13484
• Main Authors: Ebrahem, Quteba, Renganathan, Kutralanathan, Sears, Jonathan, Vasanji, Amit, Gu, Xiaorong, Lu, Liang, Salomon, Robert G., Crabb, John W., Anand-Apte, Bela
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.09.2006; National Acad Sciences
• Subjects: Adducts; Aged, 80 and over; Allantois - blood supply; Angiogenesis; Animals; Antibodies; Biological Sciences; Bruch Membrane - chemistry; Cell Culture Techniques; Cell Line; Cells, Cultured; Chick Embryo; Child; Chorioallantoic membrane; Chorion - blood supply; Choroidal Neovascularization - etiology; Choroidal Neovascularization - metabolism; Cornea; Dose-Response Relationship, Drug; Eyes & eyesight; Health savings accounts; Humans; Laser Coagulation; Lasers; Macular degeneration; Macular Degeneration - metabolism; Membranes; Mice; Mice, Inbred C57BL; Middle Aged; Neovascularization, Physiologic; Oxidation; Oxidation-Reduction; Pigment Epithelium of Eye - cytology; Pigment Epithelium of Eye - drug effects; Pigment Epithelium of Eye - metabolism; Proteins; Pyrroles - chemistry; Pyrroles - metabolism; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Secretion; Serum Albumin - chemistry; Serum albumins; Vascular Endothelial Growth Factor A - analysis; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0601552103

Choroidal neovascularization (CNV), the advanced stage of agerelated 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.