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dc.contributor.authorValls-Lacalle, Laura-
dc.contributor.authorCorall Negre-Pujol-
dc.contributor.authorRodríguez, Cristina-
dc.contributor.authorVarona, Saray-
dc.contributor.authorValera-Cañellas, Antoni-
dc.contributor.authorConsegal, Marta-
dc.contributor.authorMartínez-González, José-
dc.contributor.authorRodríguez-Sinovas, Antonio-
dc.date.accessioned2020-04-17T10:50:15Z-
dc.date.available2020-04-17T10:50:15Z-
dc.date.issued2019-10-22-
dc.identifierdoi: 10.3390/cells8101299-
dc.identifierissn: 2073-4409-
dc.identifiere-issn: 2073-4409-
dc.identifier.citationCells 8(10): 1299 (2019)-
dc.identifier.urihttp://hdl.handle.net/10261/208082-
dc.description.abstractConnexin 43 (Cx43) is essential for cardiac electrical coupling, but its effects on myocardial fibrosis is controversial. Here, we analyzed the role of Cx43 in myocardial fibrosis caused by angiotensin II (AngII) using Cx43fl/fl and Cx43Cre-ER(T)/fl inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele. Myocardial collagen content was enhanced by AngII in all groups (n = 8-10/group, p < 0.05). However, animals with partial Cx43 deficiency (vehicle-treated Cx43Cre-ER(T)/fl) had a significantly higher AngII-induced collagen accumulation that reverted when treated with 4-OHT, which abolished Cx43 expression. The exaggerated fibrotic response to AngII in partially deficient Cx43Cre-ER(T)/fl mice was associated with enhanced p38 MAPK activation and was not evident in Cx43 heterozygous (Cx43+/-) mice. In contrast, normalization of interstitial collagen in 4-OHT-treated Cx43Cre-ER(T)/fl animals correlated with enhanced MMP-9 activity, IL-6 and NOX2 mRNA expression, and macrophage content, and with reduced alpha-SMA and SM22alpha in isolated fibroblasts. In conclusion, our data demonstrates an exaggerated, p38 MAPK-dependent, fibrotic response to AngII in partially deficient Cx43Cre-ER(T)/fl mice, and a paradoxical normalization of collagen deposition in animals with an almost complete Cx43 ablation, an effect associated with increased MMP-9 activity and inflammatory response and reduced fibroblasts differentiation.-
dc.description.sponsorshipThis work was supported by Fundació La Marató de TV3 (nº. 201536-10), the Spanish Instituto de Salud Carlos III (grants PI18/0919 and CIBERCV) andMinisterio de Ciencia, Innovación y Universidades (grant RTI2018-094727-B-100), cofinanced by the European Regional Development Fund (ERDF-FEDER, a way to build Europe), and Agencia de Gestió d’Ajuts Universitaris i de Recerca (AGAUR; program of Support to Research Groups, Refs. 2017-SGR-1807 and 2017-SGR-00333).. Antonio Rodríguez-Sinovas has a consolidated Miguel Servet contract.-
dc.languageeng-
dc.publisherMolecular Diversity Preservation International-
dc.relationMICIU/ICTI2017-2020/RTI2018-094727-B-100-
dc.relationRTI2018-094727-B-100/AEI/10.13039/501100011033-
dc.relation.isversionofPublisher's version-
dc.rightsopenAccess-
dc.subjectAngiotensin II-
dc.subjectFibrosis-
dc.subjectCollagen-
dc.subjectConnexin 43-
dc.subjectHypertrophy-
dc.titleOpposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis-
dc.typeartículo-
dc.relation.publisherversionhttp://dx.doi.org/10.3390/cells8101299-
dc.date.updated2020-04-17T10:50:16Z-
dc.rights.licensehttp://creativecommons.org/licenses/by/4.0/-
dc.contributor.funderFundació La Marató de TV3-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España)-
dc.contributor.funderAgencia Estatal de Investigación (España)-
dc.contributor.funderEuropean Commission-
dc.contributor.funderGeneralitat de Catalunya-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100002809es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100011033es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100008666es_ES
dc.contributor.orcidRodríguez, Cristina [0000-0002-6472-5647]-
dc.contributor.orcidRodríguez-Sinovas, Antonio [0000-0003-2930-8773]-
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