Protective effect of diphenyl diselenide against peroxynitrite-mediated endothelial cell death: A comparison with ebselen

•Organoselenium compounds efficiently protect endothelial cells against peroxynitrite toxicity.•The cytopropective effect of diphenyl diselenide could be related with its ability to activate the Nrf-2 cognate genes.•Diphenyl diselenide increases the expression and activity of GPx and the GSH content in endothelial cells. Excess production of superoxide (O2−) and nitric oxide (NO) in blood vessel walls may occur early in atherogenesis leading to the formation of peroxynitrite, a strong oxidant and nitrating agent. This study was designed to determine the effect of diphenyl diselenide (PhSe)2, a synthetic organoselenium compound, in comparison with ebselen, on peroxynitrite-mediated endothelial damage. Experimental results showed that pre-incubation of BAEC (24h) with low concentrations of (PhSe)2 (0.5 and 1μM) protected the cells from peroxynitrite-dependent apoptosis and protein tyrosine nitration. The intracellular levels of GSH were almost completely depleted by peroxynitrite and, although the compounds did not restore its normal levels, (PhSe)2per se significantly increased GSH in a concentration-dependent manner. Moreover, (PhSe)2, which was about two times more active as a GPx mimic than ebselen, induced a significantly higher increase in both cellular GPx expression and activity. Taking into account the kinetics of the reaction between peroxynitrite and (PhSe)2, our data indicate that (PhSe)2 protects BAEC against peroxynitrite-mediated cell damage not by a direct reaction, but rather by increasing cellular GPx expression as a consequence of enhanced nuclear translocation of Nrf-2, which together with the increase in intracellular GSH, may work catalytically to reduce peroxynitrite to nitrite.