Protein carbamylation links inflammation, smoking, uremia and atherogenesis.
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.
Wang
Zeneng
Z
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Nicholls
Stephen J
SJ
Rodriguez
E Rene
ER
Kummu
Outi
O
Hörkkö
Sohvi
S
Barnard
John
J
Reynolds
Wanda F
WF
Topol
Eric J
EJ
DiDonato
Joseph A
JA
Hazen
Stanley L
SL
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001798:Blood Proteins / Q000378:metabolism*; D002219:Carbamates / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis; D002956:Citrulline / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000097:blood; D002986:Clinical Trials as Topic; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology; D003485:Cyanates / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005487:Foam Cells / Q000166:cytology; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D019169:Jurkat Cells; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D011237:Predictive Value of Tests; D011499:Protein Processing, Post-Translational; D011973:Receptors, LDL / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D012907:Smoking / Q000378:metabolism*; D014511:Uremia / Q000097:blood*