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Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis

Connexin 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 Cx43(fl/fl) and Cx43(Cre-ER(T)/fl) inducible knock-out (Cx43 content: 50%) mice t...

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Autores principales: Valls-Lacalle, Laura, Negre-Pujol, Corall, Rodríguez, Cristina, Varona, Saray, Valera-Cañellas, Antoni, Consegal, Marta, Martínez-González, Jose, Rodríguez-Sinovas, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830333/
https://www.ncbi.nlm.nih.gov/pubmed/31652649
http://dx.doi.org/10.3390/cells8101299
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author Valls-Lacalle, Laura
Negre-Pujol, Corall
Rodríguez, Cristina
Varona, Saray
Valera-Cañellas, Antoni
Consegal, Marta
Martínez-González, Jose
Rodríguez-Sinovas, Antonio
author_facet Valls-Lacalle, Laura
Negre-Pujol, Corall
Rodríguez, Cristina
Varona, Saray
Valera-Cañellas, Antoni
Consegal, Marta
Martínez-González, Jose
Rodríguez-Sinovas, Antonio
author_sort Valls-Lacalle, Laura
collection PubMed
description Connexin 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 Cx43(fl/fl) and Cx43(Cre-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 Cx43(Cre-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 Cx43(Cre-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 Cx43(Cre-ER(T)/fl) animals correlated with enhanced MMP-9 activity, IL-6 and NOX2 mRNA expression, and macrophage content, and with reduced α-SMA and SM22α in isolated fibroblasts. In conclusion, our data demonstrates an exaggerated, p38 MAPK-dependent, fibrotic response to AngII in partially deficient Cx43(Cre-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.
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spelling pubmed-68303332019-11-20 Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis Valls-Lacalle, Laura Negre-Pujol, Corall Rodríguez, Cristina Varona, Saray Valera-Cañellas, Antoni Consegal, Marta Martínez-González, Jose Rodríguez-Sinovas, Antonio Cells Article Connexin 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 Cx43(fl/fl) and Cx43(Cre-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 Cx43(Cre-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 Cx43(Cre-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 Cx43(Cre-ER(T)/fl) animals correlated with enhanced MMP-9 activity, IL-6 and NOX2 mRNA expression, and macrophage content, and with reduced α-SMA and SM22α in isolated fibroblasts. In conclusion, our data demonstrates an exaggerated, p38 MAPK-dependent, fibrotic response to AngII in partially deficient Cx43(Cre-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. MDPI 2019-10-22 /pmc/articles/PMC6830333/ /pubmed/31652649 http://dx.doi.org/10.3390/cells8101299 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Valls-Lacalle, Laura
Negre-Pujol, Corall
Rodríguez, Cristina
Varona, Saray
Valera-Cañellas, Antoni
Consegal, Marta
Martínez-González, Jose
Rodríguez-Sinovas, Antonio
Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis
title Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis
title_full Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis
title_fullStr Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis
title_full_unstemmed Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis
title_short Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis
title_sort opposite effects of moderate and extreme cx43 deficiency in conditional cx43-deficient mice on angiotensin ii-induced cardiac fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830333/
https://www.ncbi.nlm.nih.gov/pubmed/31652649
http://dx.doi.org/10.3390/cells8101299
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