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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration
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Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration

机译：羧乙基吡咯氧化蛋白修饰刺激新生血管形成：与年龄相关的黄斑变性的意义

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摘要

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 angiogen-esis 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.
机译：脉络膜新血管形成（CNV）是年龄相关性黄斑变性（AMD）的晚期，占AMD视力丧失的80％以上。羧乙基吡咯（CEP）蛋白修饰是由含二十二碳六烯酸酯的脂质氧化而独特产生的，在AMD眼睛的Bruch膜中更为丰富。我们测试了CEP蛋白加合物刺激血管生成的假说，并可能有助于AMD中CNV的假说。化学修饰人血清白蛋白（HSA）或乙酰基-Gly-Lys-O-甲基酯（二肽）以产生CEP修饰的HSA（CEP-HSA）或CEP-二肽。通过使用鸡绒膜尿囊膜和大鼠角膜微囊测定法证明了CEP-HSA和CEP-二肽的体内血管生成特性。皮摩尔的CEP-HSA和CEP-二肽含量低会刺激新血管形成。单克隆抗CEP抗体中和了CEP-HSA刺激的角膜缘血管生长，而抗VEGF抗体仅部分中和了血管生长。视网膜下注射CEP修饰的小鼠血清白蛋白会加剧小鼠的激光诱导CNV。用CEP-二肽或CEP-HSA体外治疗人视网膜色素上皮细胞不会诱导VEGF分泌增加。总体而言，这些结果表明，CEP诱导的血管生成利用了VEGF非依赖性途径，并且抗CEP的治疗方式可能在限制AMD CNV方面具有价值。

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