蛋白质甲酰化可预测冠状动脉硬化的风险


Title:
Protein carbamylation links inflammation, smoking, uremia and atherogenesis

DOI:
10.1038/nm1637

Abstract:
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.

All Authors:
Zeneng Wang,Stephen J Nicholls,E Rene Rodriguez,Outi Kummu,John Barnard,Wanda F Reynolds,Eric J Topol,Joseph A DiDonato,Stanley L Hazen,Sohvi Hörkkö

First Authors:
Zeneng Wang

Correspondence:
Stanley L Hazen


摘要:

       蛋白质甲酰化在肾脏疾病后期可导致血管机能障碍。吸烟者血液中显著增加的硫氰酸盐被髓过氧化物酶氧化是甲酰化的一种新机制。髓过氧化物酶可将LDL转化为配体识别巨噬细胞消除受体A1,增加胆固醇并形成泡沫细胞。两个独立的临床实验表明血浆中蛋白质结合的高瓜氨酸可预测冠状动脉疾病的风险。

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