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dc.contributor.author
Sepúlveda, Marisa Noemí
dc.contributor.author
Gonano, Luis Alberto
dc.contributor.author
Viotti, Manuel
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Morell, Malena
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Blanco, Paula Graciela
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López Alarcón, Maria Micaela
dc.contributor.author
Peroba Ramos, Isalira
dc.contributor.author
Bastos Carvalho, Adriana
dc.contributor.author
Medei, Emiliano
dc.contributor.author
Vila Petroff, Martin Gerarde
dc.date.available
2018-07-05T16:48:32Z
dc.date.issued
2017-04
dc.identifier.citation
Sepúlveda, Marisa Noemí; Gonano, Luis Alberto; Viotti, Manuel; Morell, Malena; Blanco, Paula Graciela; et al.; Calcium/Calmodulin Protein Kinase II-Dependent Ryanodine Receptor Phosphorylation Mediates Cardiac Contractile Dysfunction Associated with Sepsis; Lippincott Williams; Critical Care Medicine.; 45; 4; 4-2017; e399-e408
dc.identifier.issn
0090-3493
dc.identifier.uri
http://hdl.handle.net/11336/51353
dc.description.abstract
Objectives: Sepsis is associated with cardiac contractile dysfunction attributed to alterations in Ca2+ handling. We examined the subcellular mechanisms involved in sarcoplasmic reticulum Ca2+ loss that mediate altered Ca2+ handling and contractile dysfunction associated with sepsis. Design: Randomized controlled trial. Setting: Research laboratory Subjects: Male wild type and transgenic mice Interventions: We induced sepsis in mice using the colon ascendens stent peritonitis model. Measurements and Main Results: Twenty-four hours after colon ascendens stent peritonitis surgery, we observed that wild type mice had significantly elevated proinflammatory cytokine levels, reduced ejection fraction, and fractional shortening (ejection fraction %, 54.76 ± 0.67; fractional shortening %, 27.53 ± 0.50) compared with sham controls (ejection fraction %, 73.57 ± 0.20; fractional shortening %, 46.75 ± 0.38). At the cardiac myocyte level, colon ascendens stent peritonitis cells showed reduced cell shortening, Ca2+ transient amplitude and sarcoplasmic reticulum Ca2+ content compared with sham cardiomyocytes. Colon ascendens stent peritonitis hearts showed a significant increase in oxidation-dependent calcium and calmodulin-dependent protein kinase II activity, which could be prevented by pretreating animals with the antioxidant tempol. Pharmacologic inhibition of calcium and calmodulin-dependent protein kinase II with 2.5 μM of KN93 prevented the decrease in cell shortening, Ca2+ transient amplitude, and sarcoplasmic reticulum Ca2+ content in colon ascendens stent peritonitis myocytes. Contractile function was also preserved in colon ascendens stent peritonitis myocytes isolated from transgenic mice expressing a calcium and calmodulin-dependent protein kinase II inhibitory peptide (AC3-I) and in colon ascendens stent peritonitis myocytes isolated from mutant mice that have the ryanodine receptor 2 calcium and calmodulin-dependent protein kinase II-dependent phosphorylation site (serine 2814) mutated to alanine (S2814A). Furthermore, colon ascendens stent peritonitis S2814A mice showed preserved ejection fraction and fractional shortening (ejection fraction %, 73.06 ± 6.31; fractional shortening %, 42.33 ± 5.70) compared with sham S2814A mice (ejection fraction %, 71.60 ± 4.02; fractional shortening %, 39.63 ± 3.23). Conclusions: Results indicate that oxidation and subsequent activation of calcium and calmodulin-dependent protein kinase II has a causal role in the contractile dysfunction associated with sepsis. Calcium and calmodulin-dependent protein kinase II, through phosphorylation of the ryanodine receptor would lead to Ca2+ leak from the sarcoplasmic reticulum, reducing sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude and contractility. Development of organ-specific calcium and calmodulin-dependent protein kinase II inhibitors may result in a beneficial therapeutic strategy to ameliorate contractile dysfunction associated with sepsis.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Lippincott Williams
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
CALCIUM AND CALMODULIN-DEPENDENT PROTEIN KINASE II
dc.subject
CONTRACTILE DYSFUNCTION
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RYANODINE RECEPTORS
dc.subject
SEPSIS
dc.subject.classification
Inmunología
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Calcium/Calmodulin Protein Kinase II-Dependent Ryanodine Receptor Phosphorylation Mediates Cardiac Contractile Dysfunction Associated with Sepsis
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-06-07T17:56:28Z
dc.journal.volume
45
dc.journal.number
4
dc.journal.pagination
e399-e408
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Philadelphia
dc.description.fil
Fil: Sepúlveda, Marisa Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
dc.description.fil
Fil: Gonano, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
dc.description.fil
Fil: Viotti, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
dc.description.fil
Fil: Morell, Malena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
dc.description.fil
Fil: Blanco, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina
dc.description.fil
Fil: López Alarcón, Maria Micaela. Universidade Federal do Rio de Janeiro; Brasil
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Fil: Peroba Ramos, Isalira. Universidade Federal do Rio de Janeiro; Brasil
dc.description.fil
Fil: Bastos Carvalho, Adriana. Universidade Federal do Rio de Janeiro; Brasil
dc.description.fil
Fil: Medei, Emiliano. Universidade Federal do Rio de Janeiro; Brasil
dc.description.fil
Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
dc.journal.title
Critical Care Medicine.
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1097/CCM.0000000000002101
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://insights.ovid.com/crossref?an=00003246-201704000-00038
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