P 038 - Role of the myeloperoxidase oxidant hypothiocyanous acid (HOSCN) in the adaption of cells to oxidative stress during inflammation

Abstract

A host of chronic inflammatory diseases are accelerated by the formation of the powerful oxidant hypochlorous acid (HOCl) by myeloperoxidase (MPO). In the presence of thiocyanate (SCN-), the production of HOCl by MPO is decreased in favour of the formation of a milder oxidant, hypothiocyanous acid (HOSCN). Unlike HOCl, HOSCN reacts selectively with thiols to result in reversible modifications that can be repaired, potentially reducing the extent of MPO-induced damage during inflammation. In this study, we show that exposure of macrophages, a key inflammatory cell type, to HOSCN results in the reversible modification of multiple metabolic proteins, leading to decreased glycolysis, oxidative phosphorylation and reduced formation of ATP, NADH and lactate. HOSCN was able to re-route the glycolytic flux through the pentose phosphate pathway, which elevated the production of NADPH by increasing glucose 6-phosphate dehydrogenase activity. This glycolytic switch was not observed on exposure of macrophages to HOCl. These results suggest that HOSCN may induce an adaptive response in the macrophages, whereby the increased NADPH could increase the capacity of the cellular enzymatic antioxidant systems to deal with an oxidative insult. These data provide new insight into pathways by which SCN- could modulate MPO-induced damage in inflammatory diseases, including atherosclerosis.