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dc.contributor.CRUESPUniversidade Estadual de Campinaspt_BR
dc.typeArtigo de periódicopt_BR
dc.titleOxidative stress in hypercholesterolemic LDL (low-density lipoprotein) receptor knockout mice is associated with low content of mitochondrial NADP-linked substrates and is partially reversed by citrate replacementpt_BR
dc.contributor.authorPaim, BApt_BR
dc.contributor.authorVelho, JApt_BR
dc.contributor.authorCastilho, RFpt_BR
dc.contributor.authorOliveira, HCFpt_BR
dc.contributor.authorVercesi, AEpt_BR
unicamp.authorPaim, Bruno A. Velho, Jesus A. Castilho, Roger F. Vercesi, Anibal E. Univ Estadual Campinas, Fac Ciencias Med, Dept Clin Pathol, BR-13083887 Campinas, SP, Brazilpt_BR
unicamp.authorOliveira, Helena C. F. Univ Estadual Campinas, Inst Biol, Dept Fisiol & Biofis, BR-13083970 Campinas, SP, Brazilpt_BR
dc.subjectLDL receptorpt_BR
dc.subjectreactive oxygen speciespt_BR
dc.subjectpyridine nucleotide oxidationpt_BR
dc.subject.wosRat-liver Mitochondriapt_BR
dc.subject.wosPermeability Transition Porept_BR
dc.subject.wosMembrane Permeabilizationpt_BR
dc.subject.wosSuperoxide Anionpt_BR
dc.subject.wosRedox Statept_BR
dc.description.abstractWe have previously proposed that hypercholesterolemic LDL receptor knockout (k/o) mice mitochondria possess a lower antioxidant capacity due to a large consumption of reducing equivalents from NADPH to sustain high rates of lipogenesis. In this work, we tested the hypothesis that this k/o mice mitochondrial oxidative stress results from the depletion of NADPH-linked substrates. In addition, the oxidative stress was further characterized by showing a lower mitochondrial GSH/GSSG ratio and a higher liver content of protein carbonyls as compared to controls. The activity of the antioxidant enzyme system glutathione reductase/peroxidase did not differ in k/o and control mitochondria. The faster spontaneous oxidation of endogenous NADPH in the k/o mitochondria was prevented by the addition of exogenous catalase, indicating that this oxidation is mediated by mitochondrially generated H2O2. The higher rate of H2O2 production was also prevented by the addition of exogenous isocitrate that maintains NADP fully reduced. The hypothesis that high rates of lipogenesis in the k/o cells decrease mitochondrial NADPH/NADP(+) ratio due to consumption of NADPH-linked substrates was supported by two findings: (i) oxygen consumption supported by endogenous NAD(P)H-linked substrates was slower in k/o than in control mitochondria, but was similar in the presence of exogenous isocitrate; (ii) in vivo treatment of k/o mice with sodium citrate/citric acid drinking solution for 2 weeks partially restored both the rate of oxygen consumption supported by NAD(P)H-linked substrates and the mitochondrial capacity to sustain reduced NADPH. In conclusion, the data demonstrate that the mitochondrial oxidative stress in hypercholesterolemic LDL receptor knockout mice is the result of a low content of mitochondrial NADPH-linked substrates in the intact animal that can be, at least in part, replenished by oral administration of citrate. (c) 2007 Elsevier Inc. All rights
dc.relation.ispartofFree Radical Biology And Medicinept_BR
dc.relation.ispartofabbreviationFree Radic. Biol. Med.pt_BR
dc.publisher.cityNew Yorkpt_BR
dc.publisherElsevier Science Incpt_BR 1pt_BR
dc.identifier.citationFree Radical Biology And Medicine. Elsevier Science Inc, v. 44, n. 3, n. 444, n. 451, 2008.pt_BR
dc.sourceWeb of Sciencept_BR
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