title: Protective effect of diphenyl diselenide against peroxynitrite-mediated endothelial cell death: a comparison with ebselen.
abstract: 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 (24 h) with low concentrations of (PhSe)₂ (0.5 and 1 μM) 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)₂ per 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.
authors.affiliation: Laboratorio de Bioquímica, Faculdade de Farmácia, and Center for Neurosciences and Cell Biology Universidade de Coimbra, Coimbra 3000-295, Portugal. andrezadebem@ccb.ufsc.br
authors.forename: Andreza Fabro
authors.initials: AF
authors.lastname: de Bem
authors.forename: Bianca
authors.initials: B
authors.lastname: Fiuza
authors.forename: Pablo
authors.initials: P
authors.lastname: Calcerrada
authors.forename: Paula M
authors.initials: PM
authors.lastname: Brito
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Peluffo
authors.forename: Teresa C P
authors.initials: TC
authors.lastname: Dinis
authors.forename: Madia
authors.initials: M
authors.lastname: Trujillo
authors.forename: João B T
authors.initials: JB
authors.lastname: Rocha
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.forename: Leonor M
authors.initials: LM
authors.lastname: Almeida
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001393:Azoles / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000494:pharmacology*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D054833:Isoindoles; D051267:NF-E2-Related Factor 2; D016566:Organoselenium Compounds / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000633:toxicity*; D020011:Protective Agents / Q000494:pharmacology*
chemical_list: D001393:Azoles; D001555:Benzene Derivatives; D054833:Isoindoles; D051267:NF-E2-Related Factor 2; D016566:Organoselenium Compounds; D020011:Protective Agents; D030421:Peroxynitrous Acid; C061132:diphenyldiselenide; C042986:ebselen; D005979:Glutathione Peroxidase; D005978:Glutathione