Oxidative 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 Replacement.

dc.creatorPaim, Bruno A
dc.creatorVelho, Jesus A
dc.creatorCastilho, Roger F
dc.creatorOliveira, Helena C F
dc.creatorVercesi, Aníbal E
dc.date2008-Feb
dc.date2015-11-27T13:13:12Z
dc.date2015-11-27T13:13:12Z
dc.date.accessioned2018-03-29T01:07:31Z
dc.date.available2018-03-29T01:07:31Z
dc.identifierFree Radical Biology & Medicine. v. 44, n. 3, p. 444-51, 2008-Feb.
dc.identifier0891-5849
dc.identifier10.1016/j.freeradbiomed.2007.10.005
dc.identifierhttp://www.ncbi.nlm.nih.gov/pubmed/17991444
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/197983
dc.identifier17991444
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1298216
dc.descriptionWe 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 H(2)O(2). The higher rate of H(2)O(2) 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.
dc.description44
dc.description444-51
dc.languageeng
dc.relationFree Radical Biology & Medicine
dc.relationFree Radic. Biol. Med.
dc.rightsfechado
dc.rights
dc.sourcePubMed
dc.subjectAnimals
dc.subjectCitric Acid
dc.subjectGlutathione
dc.subjectGlutathione Disulfide
dc.subjectGlutathione Reductase
dc.subjectHydrogen Peroxide
dc.subjectHypercholesterolemia
dc.subjectMice
dc.subjectMice, Knockout
dc.subjectMitochondria, Liver
dc.subjectNadp
dc.subjectOxidative Stress
dc.subjectPeroxidase
dc.subjectReceptors, Ldl
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 Replacement.
dc.typeArtículos de revistas


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