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dc.contributor.author
Toledo, Flavia Daniela
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dc.contributor.author
Perez, Leonardo Martin
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dc.contributor.author
Basiglio, Cecilia Lorena
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dc.contributor.author
Ochoa, Justina Elena
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dc.contributor.author
Sanchez Pozzi, Enrique Juan
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dc.contributor.author
Roma, Marcelo Gabriel
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dc.date.available
2016-06-08T14:01:48Z
dc.date.issued
2014-03
dc.identifier.citation
Toledo, Flavia Daniela; Perez, Leonardo Martin; Basiglio, Cecilia Lorena; Ochoa, Justina Elena; Sanchez Pozzi, Enrique Juan; et al.; The Ca2+-calmodulin-Ca2+/calmodulin- dependent protein kinase II signaling pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in isolated rat hepatocytes; Springer; Archives of Toxicology; 88; 9; 3-2014; 1695-1709
dc.identifier.issn
0340-5761
dc.identifier.uri
http://hdl.handle.net/11336/6104
dc.description.abstract
Oxidative stress (OS) is a common event in most hepatopathies, leading to mitochondrial permeability transition pore (MPTP) formation and further exacerbation of both OS from mitochondrial origin and cell death. Intracellular Ca2+ increase plays 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) signaling pathway is involved in this process, by using tert-butyl hydroperoxide (tBOOH) as a pro-oxidant, 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 cyclosporin A (CsA)-sensitive manner, revealing the involvement of MPTPs in tBOOH-induced radical oxygen species (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 OS-induced MPTP formation and the subsequent exacerbation of OS from mitochondrial origin and apoptotic cell death.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Springer
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Oxidative Stress
dc.subject
Tert-Butyl Hydroperoxide
dc.subject
Ca2+/Calmodulin-Dependent Protein Kinase Ii
dc.subject
Mitochondrial Permeability Transition Pore
dc.subject
Apoptosis
dc.subject
Cytochrome C
dc.subject.classification
Bioquímica y Biología Molecular
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dc.subject.classification
Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
The Ca2+-calmodulin-Ca2+/calmodulin- dependent protein kinase II signaling pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in isolated rat hepatocytes
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-06-01T14:01:32Z
dc.journal.volume
88
dc.journal.number
9
dc.journal.pagination
1695-1709
dc.journal.pais
Alemania
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dc.journal.ciudad
Berlin
dc.description.fil
Fil: Toledo, Flavia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
dc.description.fil
Fil: Perez, Leonardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
dc.description.fil
Fil: Basiglio, Cecilia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
dc.description.fil
Fil: Ochoa, Justina Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
dc.description.fil
Fil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
dc.description.fil
Fil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina
dc.journal.title
Archives of Toxicology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://link.springer.com/article/10.1007%2Fs00204-014-1219-5
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/10.1007/s00204-014-1219-5
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1007/s00204-014-1219-5
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