Wang Zeneng, Nicholls Stephen J, Rodriguez E Rene, Kummu Outi, Hörkkö Sohvi, Barnard John, Reynolds Wanda F, Topol Eric J, DiDonato Joseph A, Hazen Stanley L
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Nat Med. 2007 Oct;13(10):1176-84. doi: 10.1038/nm1637. Epub 2007 Sep 9.
Post-translational modification and functional impairment of proteins through carbamylation is thought to promote vascular dysfunction during end-stage renal disease. Cyanate, a reactive species in equilibrium with urea, carbamylates protein lysine residues to form epsilon-carbamyllysine (homocitrulline), altering protein structure and function. We now report the discovery of an alternative and quantitatively dominant mechanism for cyanate formation and protein carbamylation at sites of inflammation and atherosclerotic plaque: myeloperoxidase-catalyzed oxidation of thiocyanate, an anion abundant in blood whose levels are elevated in smokers. We also show that myeloperoxidase-catalyzed lipoprotein carbamylation facilitates multiple pro-atherosclerotic activities, including conversion of low-density lipoprotein into a ligand for macrophage scavenger receptor A1 recognition, cholesterol accumulation and foam-cell formation. In two separate clinical studies (combined n = 1,000 subjects), plasma levels of protein-bound homocitrulline independently predicted increased risk of coronary artery disease, future myocardial infarction, stroke and death. We propose that protein carbamylation is a mechanism linking inflammation, smoking, uremia and coronary artery disease pathogenesis.
蛋白质通过氨甲酰化发生的翻译后修饰及功能损伤被认为会在终末期肾病期间促进血管功能障碍。氰酸盐是一种与尿素呈平衡状态的反应性物质，它会使蛋白质赖氨酸残基氨甲酰化，形成ε-氨甲酰赖氨酸（高瓜氨酸），从而改变蛋白质的结构和功能。我们现在报告了一种在炎症和动脉粥样硬化斑块部位形成氰酸盐及蛋白质氨甲酰化的替代机制，且该机制在数量上占主导地位：髓过氧化物酶催化硫氰酸盐氧化，硫氰酸盐是血液中丰富的一种阴离子，吸烟者体内其水平会升高。我们还表明，髓过氧化物酶催化的脂蛋白氨甲酰化促进多种促动脉粥样硬化活动，包括将低密度脂蛋白转化为巨噬细胞清道夫受体A1识别的配体、胆固醇积累和泡沫细胞形成。在两项独立的临床研究（共纳入1000名受试者）中，与蛋白质结合的高瓜氨酸的血浆水平独立预测了冠状动脉疾病、未来心肌梗死、中风和死亡风险的增加。我们提出，蛋白质氨甲酰化是一种将炎症、吸烟、尿毒症和冠状动脉疾病发病机制联系起来的机制。
