Carboxyethylpyrrole Oxidative Protein Modifications Stimulate Neovascularization: Implications for Age-Related Macular Degeneration
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 me...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 36; pp. 13480 - 13484 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
National Academy of Sciences
05.09.2006
National Acad Sciences |
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Abstract | 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. |
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AbstractList | 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. 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. 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. 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. oxidation 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. [PUBLICATION ABSTRACT] |
Author | Vasanji, Amit Gu, Xiaorong Anand-Apte, Bela Sears, Jonathan Lu, Liang Salomon, Robert G. Renganathan, Kutralanathan Ebrahem, Quteba Crabb, John W. |
Author_xml | – sequence: 1 givenname: Quteba surname: Ebrahem fullname: Ebrahem, Quteba – sequence: 2 givenname: Kutralanathan surname: Renganathan fullname: Renganathan, Kutralanathan – sequence: 3 givenname: Jonathan surname: Sears fullname: Sears, Jonathan – sequence: 4 givenname: Amit surname: Vasanji fullname: Vasanji, Amit – sequence: 5 givenname: Xiaorong surname: Gu fullname: Gu, Xiaorong – sequence: 6 givenname: Liang surname: Lu fullname: Lu, Liang – sequence: 7 givenname: Robert G. surname: Salomon fullname: Salomon, Robert G. – sequence: 8 givenname: John W. surname: Crabb fullname: Crabb, John W. – sequence: 9 givenname: Bela surname: Anand-Apte fullname: Anand-Apte, Bela |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16938854$$D View this record in MEDLINE/PubMed |
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Notes | Edited by Mark T. Keating, Novartis Institutes for Biomedical Research, Cambridge, MA, and approved July 17, 2006 Q.E. and K.R. contributed equally to this work. Author contributions: Q.E., J.W.C., and B.A.-A. designed research; Q.E., K.R., J.S., and L.L. performed research; X.G. and R.G.S. contributed new reagents/analytic tools; Q.E., K.R., A.V., J.W.C., and B.A.-A. analyzed data; and J.W.C. and B.A.-A. wrote the paper. |
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Snippet | Choroidal neovascularization (CNV), the advanced stage of agerelated macular degeneration (AMD), accounts for > 80% of vision loss in AMD. Carboxyethylpyrrole... Choroidal neovascularization (CNV), the advanced stage of age-related macular degeneration (AMD), accounts for >80% of vision loss in AMD. Carboxyethylpyrrole... |
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SubjectTerms | 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 |
Title | Carboxyethylpyrrole Oxidative Protein Modifications Stimulate Neovascularization: Implications for Age-Related Macular Degeneration |
URI | https://www.jstor.org/stable/30050812 http://www.pnas.org/content/103/36/13480.abstract https://www.ncbi.nlm.nih.gov/pubmed/16938854 https://www.proquest.com/docview/201348272 https://pubmed.ncbi.nlm.nih.gov/PMC1569188 |
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