Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration
Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration
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DOI：
10.1073/pnas.0601552103
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发表时间：
2006-09-05
影响因子：
11.1
通讯作者：
Anand-Apte, Bela
中科院分区：
文献类型：
--
作者：
Ebrahem, Quteba;Renganathan, Kutralanathan;Anand-Apte, Bela
脉络膜新生血管（CNV）是老年性黄斑变性（AMD）的晚期，占AMD视力丧失的80%。羧基乙基吡咯（CEP）蛋白修饰是由含有二十二碳六烯酸的脂质氧化而产生的，在AMD眼睛的Bruch膜中更为丰富。我们验证了CEP蛋白加合物刺激血管生成并可能导致AMD中CNV的假设。将人血清白蛋白（HSA）或乙酰-甘氨酸-赖氨酸- o -甲酯（二肽）进行化学修饰，得到cep修饰的人血清白蛋白（CEP-HSA）或cep -二肽。通过鸡绒毛膜尿囊膜和大鼠角膜微袋实验，验证了CEP-HSA和cep -二肽的体内血管生成特性。低皮摩尔量的CEP-HSA和cep -二肽刺激新生血管。单克隆抗cep抗体可中和CEP-HSA刺激的角膜缘血管生长，而抗vegf抗体仅能部分中和血管生长。视网膜下注射cep修饰的小鼠血清白蛋白加剧了小鼠激光诱导的CNV。体外用cep -二肽或CEP-HSA处理人视网膜色素上皮细胞均未引起VEGF分泌增加。总的来说，这些结果表明cep诱导的血管生成利用vegf独立的途径，抗cep治疗方式可能对限制AMD的CNV有价值。
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.