Myeloperoxidase-derived oxidants: their Intracellular targets, defence mechanisms and role in disease

Abstract

Myeloperoxidase, a heme enzyme secreted by activated phagocytes at sites of inflammation, catalyses the oxidation of Cl- and SCN- to HOCl and HOSCN, which play an essential role in innate immunity. The misregulated production of these oxidants can be detrimental to the host. Thiocyanate is a preferred substrate of MPO, and higher SCN- levels are present in the plasma of smokers, suggesting that HOSCN formation may contribute to the enhanced risk of atherosclerosis (and other diseases) in smokers. The studies described in this thesis used both plasma samples, and the murine macrophage-like J774A.1 cells to investigate the role of HOSCN. Elevated levels of plasma SCN- positively correlated with thiol oxidation under conditions mimicking an inflammatory episode. Higher levels of plasma SCN-, in combination with low levels of MPO, correlated with lower rates of 12-year all-cause mortality, thus suggesting a protective role of SCN- under certain conditions. Cell-based experiments examined the effects of HOSCN and HOCl on NADPH-dependent antioxidant enzymes and GSH/S-glutathionylation. These studies demonstrated the inhibition of TrxR activity, oxidation and hyperoxidation of Prxs, and GSH loss following HOSCN treatment, whilst HOCl caused a significant decrease in GPx activity. This suggests the presence of intracellular defence mechanisms for different MPO-derived oxidants.