The Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocytes

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dc.citation.titleArchives of Toxicologyes
dc.citation.volume88(9)es
dc.creatorToledo, Flavia D.
dc.creatorPérez, Leonardo Martín
dc.creatorBasiglio, Cecilia Lorena
dc.creatorOchoa, Justina E.
dc.creatorSánchez Pozzi, Enrique Juan
dc.creatorRoma, Marcelo Gabriel
dc.date.accessioned2018-01-30T00:07:11Z
dc.date.available2018-01-30T00:07:11Z
dc.date.issued2014-03-11
dc.descriptionOxidative stress is a common event in most hepatopathies, leading to mitochondrial permeability transition pore (MPTP) formation and further exacerbation of both oxidative stress from mitochondrial origin and cell death. Intracellular Ca2+ elevations play a permissive role in these events, but the underlying mechanisms are poorly known. We examined in primary cultured rat hepatocytes whether the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) signalling pathway is involved in this process, by using tert-butyl hydroperoxide (tBOOH) as a pro-oxidizing, model compound. tBOOH (500 µM, 15 min) induced MPTP formation, as assessed by measuring mitochondrial membrane depolarization as a surrogate marker, and increased lipid peroxidation in a clyclosporin A (CsA)-sesitive manner, revealing the involvement of MPTPs in tBOOH-induced ROS formation. Intracellular Ca2+ sequestration with BAPTA/AM, CaM blockage with W7 or trifluoperazine, and CaMKII inhibition with KN-62 all fully prevented tBOOH-induced MPTP opening and reduced tBOOH-induced lipid peroxidation to a similar extent to CsA, suggesting that Ca2+/CaM/CaMKII signaling pathway fully mediates MPTP-mediated mitochondrial ROS generation. tBOOH induced apoptosis, as shown by flow cytometry of annexin V/propidium iodide, mitochondrial release of cytochrome c, activation of caspase-3 and increase in the Bax-to-Bcl-xL ratio, and the Ca2+/CaM/CaMKII signaling antagonists fully prevented these effects. Intramitochondrial CaM and CaMKII were partially involved in tBOOH-induced MPTP formation, since W7 and KN-62 both attenuated the tBOOH-induced, MPTP-mediated swelling of isolated mitochondria. We concluded that Ca2+/CaM/CaMKII signaling pathway is a key mediator of oxidative stress-induced induced MPTP formation, and the subsequent exacerbation of oxidative stress from mitochondrial origin and apoptotic cell death.es
dc.description.filFil: Toledo, Flavia D. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Pérez, Leonardo Martín. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Ochoa, Justina E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Sánchez Pozzi, Enrique J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.filFil: Roma, Marcelo Gabriel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina.es
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica (ANPCyT), PICT 2010-0992es
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), PIP 112-200801-00691es
dc.formatapplication/pdf
dc.format.extent1695 - 1709es
dc.identifier.issn0340-5761es
dc.identifier.urihttp://hdl.handle.net/2133/10485
dc.language.isoenges
dc.publisherSpringeres
dc.relation.publisherversionhttps://link.springer.com/article/10.1007%2Fs00204-014-1219-5es
dc.relation.publisherversion10.1002/hep.2675210.1007/s00204-014-1219-5es
dc.rightsopenAccesses
dc.rights.holderSpringeres
dc.rights.holderGerman Society for Experimental and Clinical Pharmacology and Toxicology (DGPT)es
dc.rights.holderUniversidad Nacional de Rosarioes
dc.rights.holderToledo, Flavia D.es
dc.rights.holderPérez, Leonardo M.es
dc.rights.holderBasiglio, Cecilia Lorenaes
dc.rights.holderOchoa, Justina E.es
dc.rights.holderSánchez Pozzi, Enrique J.es
dc.rights.holderRoma, Marcelo Gabrieles
dc.rights.textAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectOxidative Stresses
dc.subjecttert-Butyl Hydroperoxidees
dc.subjectCa2+/calmodulin-dependent Protein Kinase IIes
dc.subjectMitochondrial Permeability Transition Porees
dc.subjectApoptosises
dc.subjectCytochrome ces
dc.subjectCaspasases
dc.titleThe Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in rat hepatocyteses
dc.typearticle
dc.typeartículo
dc.typepublishedVersion
dc.type.collectionarticulo
dc.type.versionpublishedVersiones

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