Carbamylated Low-Density Lipoprotein and Thrombotic Risk in Chronic Kidney Disease ∗

Carbamylation is a form of post-translational modification in which cyanate/isocyanate covalently modifies nucleophilic groups on proteins (e.g., N-terminal and Ne-amine groups of lysine residues or thiol group of cysteine residues), forming a carbamyl group (1). Historically, carbamylation was believed to predominantly be fostered by uremia. This is because urea is in equilibrium with cyanate/isocyanate, and carbamylation of proteins dramatically increases with severe impairment in renal function (1). Recent studies also discovered a second pathway for generation of the reactive cyanate/isocyanate species and protein carbamylation-leukocyte heme peroxidases like myeloperoxidase (MPO) (2). MPO can use plasma levels of thiocyanate as a cosubstrate to generate cyanate and catalyze protein carbamylation. Because plasma levels of thiocyanate are heightened in smokers and in exposure to second-hand or work-place smoke, this pathway has been linked to heightened cardiovascular disease risks in subjects who smoke (2). MPO has been shown to catalyze protein carbamylation at sites of inflammation, such as within the atherosclerotic artery wall where MPO-catalyzed oxidative processes are enhanced (2). Elevated levels of carbamylated proteins in plasma or serum are associated with adverse prognosis, including enhanced mortality rate in stable cardiac patients (2), subjects with end- stage renal disease on hemodialysis (3), and in patients with chronic heart failure (4).

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