Disubstituted diaryl diselenides as potential atheroprotective compounds: Involvement of TrxR and GPx-like systems

Oxidative modifications of low-density lipoproteins (LDLs) have a determinant role in atherogenesis and the study of agents that can modulate LDL oxidation is of pharmacological and therapeutic significance. Therefore, the aim of this study was to evaluate the antioxidant effect of the disubstituted diaryl diselenides, p-methoxyl-diphenyl diselenide (p-CH(3)O-C(6)H(4)Se)(2) (DM) and p-chloro-diphenyl diselenide (p-Cl-C(6)H(4)Se)(2) (DC), on Cu(2+)-induced LDL oxidation. Both compounds caused a dose-dependent inhibition of human serum and isolated LDL oxidation evidenced by the increasing of the lag phase of lipid peroxidation and decreased the lipid oxidation rate (V(max)). The protein moieties from isolated LDL were also protected from Cu(2+)-induced oxidation. Moreover, the disubstituted diaryl diselenides efficiently decreased the oxidized LDL (ox-LDL) induced foam cell formation in J774A.1 macrophage cells. Mechanistically, we have demonstrated that the antioxidant and antiatherogenic effects of DM and DC are related to formation of their selenol intermediates (RSeH) either by a direct reaction with endogenous thiols (GPx-like activity) or via their reduction by TrxR (using NADPH as electron donor). Considering the powerful effect of DM and DC against LDL-induced toxicity, they could be considered for developing of new therapeutic approaches to preventing and treating atherosclerosis and cardiovascular diseases.