Protein carbamylation links inflammation, smoking, uremia and atherogenesis

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

Research output: Contribution to journalArticle

449 Citations (Scopus)

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 ε-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.

Original languageEnglish
Pages (from-to)1176-1184
Number of pages9
JournalNature Medicine
Volume13
Issue number10
DOIs
Publication statusPublished - 1 Oct 2007

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wang, Z., Nicholls, S., Rodriguez, E. R., Kummu, O., Hörkkö, S., Barnard, J., ... Hazen, S. L. (2007). Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nature Medicine, 13(10), 1176-1184. https://doi.org/10.1038/nm1637