Pathways of myeloperoxidase-induced cellular damage in atherosclerosis

Abstract

The formation of hypochlorous acid (HOCl) by myeloperoxidase (MPO) during chronic inflammation plays a key role in the development of atherosclerosis. HOCl is a powerful oxidant that causes extensive tissue damage. In the presence of thiocyanate (SCN-), the production of HOCl by MPO is decreased by the formation of hypothiocyanous acid (HOSCN), which is a milder, thiol-specific, oxidant. It has been proposed that SCN- may reduce the extent of MPO-induced damage during inflammation, but SCN- is elevated in the plasma of smokers, who are at greater risk of atherosclerosis. In this study, we compared the reactivity of HOCl and HOSCN with macrophages, endothelial cells, and smooth muscle cells, which are involved in the progression of atherosclerosis. The sensitivity and responses to each oxidant vary with cell and treatment conditions, but culminate in altered calcium fluxes, mitochondrial dysfunction, release of cytokines and cell death by apoptosis and necrosis. We show that HOSCN can have a dual role, acting in both a pro-inflammatory and protective capacity, with repair of thiols and altered metabolic flux promoting cell survival and adaption to stress. Our data provide new insight into how SCN- could modulate MPO-induced damage and influence the development of atherosclerosis.