Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA.
Exp Eye Res. 2010 May;90(5):564-71. doi: 10.1016/j.exer.2010.01.014. Epub 2010 Feb 12.
Age-related macular degeneration (AMD) is a disease leading to severe visual loss and legal blindness in the elderly population. The pathophysiology of AMD is complex and may include genetic predispositions, accumulation of lipofuscin and drusen, local inflammation and neovascularization. Recently four independent research groups have identified a commonly inherited variant (Y402H) of the complement factor H gene in the genome from different groups of AMD patients. The Y402H variant of CFH significantly increases the risk of AMD and links the genetics of the disease with inflammation. During inflammation there is activation of inducible nitric oxide synthase and release of nitric oxide, which in principal could lead to non-enzymatic nitration within extracellular deposits and/or intrinsic extracellular matrix protein components of human Bruch's membrane. We have identified two biomarkers for non-enzymatic nitration in aged human Bruch's membrane, indicative of inflammation, that include 3-nitrotyrosine identified in Bruch's membrane preparations and nitrated A2E from the lipid soluble extract of the Bruch's membrane preparation. Approximately 30-40 times more A2E is observed in samples of the organic soluble extract of lipofuscin compared to the extract of Bruch's membrane. It is of interest to note that although A2E is a major constituent of RPE lipofuscin, nitrated A2E could not be detected in RPE extracts. We show here that nitro-A2E is a specific biomarker of nitrosative stress in Bruch's membrane and its concentration correlates directly with tissue age.
年龄相关性黄斑变性（AMD）是一种导致老年人群视力严重丧失和法定失明的疾病。AMD 的病理生理学非常复杂，可能包括遗传易感性、脂褐素和玻璃膜疣的积累、局部炎症和新生血管形成。最近，四个独立的研究小组在不同 AMD 患者群体的基因组中发现了补体因子 H 基因的一个常见遗传变异（Y402H）。CFH 的 Y402H 变异显著增加了 AMD 的风险，并将疾病的遗传学与炎症联系起来。在炎症过程中，诱导型一氧化氮合酶被激活并释放一氧化氮，这可能导致细胞外沉积物和/或人布鲁赫膜固有细胞外基质蛋白成分中的非酶促硝化。我们已经在老化的人布鲁赫膜中鉴定出两种非酶促硝化的生物标志物，表明存在炎症，其中包括在布鲁赫膜制剂中鉴定出的 3-硝基酪氨酸和来自布鲁赫膜制剂脂溶性提取物的硝化 A2E。与布鲁赫膜提取物相比，在脂褐素的有机可溶性提取物中观察到大约 30-40 倍更多的 A2E。值得注意的是，尽管 A2E 是 RPE 脂褐素的主要成分，但在 RPE 提取物中无法检测到硝化 A2E。我们在这里表明，硝基-A2E 是布鲁赫膜中硝化应激的特异性生物标志物，其浓度与组织年龄直接相关。
