Abstract
Smokers have an elevated risk of atherosclerosis but the origins of this elevated risk are incompletely defined, though evidence supports an accumulation of the oxidant-generating enzyme myeloperoxidase (MPO) in the inflamed artery wall. We hypothesized that smokers would have a high level of thiocyanate (SCN−), a preferred substrate for MPO, which in turn would predispose to thiol oxidation, an established independent risk factor for atherosclerosis. In this study it is shown that on exposure to MPO/H2O2, thiols on plasma proteins from nonsmokers were increasingly oxidized with increasing added SCN− concentrations. Plasma from smokers contained significantly higher endogenous levels of SCN− than that from nonsmokers (131±31 vs 40±24μM, P<0.0001). When plasma from smokers and nonsmokers was exposed to MPO/H2O2-stimulated oxidation, a strong positive correlation (r=0.8139, P<0.0001) between the extent of thiol oxidation and the plasma SCN− concentrations was observed. Computational calculations indicate a changeover from HOCl to HOSCN as the major MPO-generated oxidant in plasma, with increasing SCN− levels. These data indicate that plasma SCN− levels are a key determinant of the extent of thiol oxidation on plasma proteins induced by MPO, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage to proteins in smokers.
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