Carbamylation of proteins through reactive cyanate has been demonstrated to 
predict an increased cardiovascular risk. Cyanate is formed in vivo by breakdown 
of urea and at sites of inflammation by the phagocyte protein myeloperoxidase. 
Because myeloperoxidase (MPO) associates with high-density lipoprotein (HDL) in 
human atherosclerotic intima, we examined in the present study whether cyanate 
specifically targets HDL. Mass spectrometry analysis revealed that protein 
carbamylation is a major posttranslational modification of HDL. The 
carbamyllysine content of lesion-derived HDL was more than 20-fold higher in 
comparison with 3-chlorotyrosine levels, a specific oxidation product of MPO. 
Notably, the carbamyllysine content of lesion-derived HDL was five- to eightfold 
higher when compared with lesion-derived low-density lipoprotein (LDL) or total 
lesion protein and increased with lesion severity. The carbamyllysine content of 
HDL, but not of LDL, correlated with levels of 3-chlorotyrosine, suggesting that 
MPO mediated carbamylation in the vessel wall. Remarkably, one carbamyllysine 
residue per HDL-associated apolipoprotein A-I was sufficient to induce 
cholesterol accumulation and lipid-droplet formation in macrophages through a 
pathway requiring the HDL-receptor scavenger receptor class B, type I. The 
present results raise the possibility that HDL carbamylation contributes to foam 
cell formation in atherosclerotic lesions.