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<sup>fl/fl</sup> and Cx43<sup>Cre-ER(T)/fl</sup> indu...
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MDPI AG
2019-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/10/1299 |
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| author | Laura Valls-Lacalle Corall Negre-Pujol Cristina Rodríguez Saray Varona Antoni Valera-Cañellas Marta Consegal Jose Martínez-González Antonio Rodríguez-Sinovas |
| author_facet | Laura Valls-Lacalle Corall Negre-Pujol Cristina Rodríguez Saray Varona Antoni Valera-Cañellas Marta Consegal Jose Martínez-González Antonio Rodríguez-Sinovas |
| author_sort | Laura Valls-Lacalle |
| collection | DOAJ |
| 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<sup>fl/fl</sup> and Cx43<sup>Cre-ER(T)/fl</sup> 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, <i>p</i> < 0.05). However, animals with partial Cx43 deficiency (vehicle-treated Cx43<sup>Cre-ER(T)/fl</sup>) 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<sup>Cre-ER(T)/fl</sup> mice was associated with enhanced p38 MAPK activation and was not evident in Cx43 heterozygous (Cx43<sup>+/-</sup>) mice. In contrast, normalization of interstitial collagen in 4-OHT-treated Cx43<sup>Cre-ER(T)/fl</sup> 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<sup>Cre-ER(T)/fl</sup> 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. |
| first_indexed | 2024-03-12T20:15:51Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T20:15:51Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
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| spelling | doaj.art-b6fc3ee34fdd4a7bb71f25560ba21c6a2023-08-02T01:21:51ZengMDPI AGCells2073-44092019-10-01810129910.3390/cells8101299cells8101299Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac FibrosisLaura Valls-Lacalle0Corall Negre-Pujol1Cristina Rodríguez2Saray Varona3Antoni Valera-Cañellas4Marta Consegal5Jose Martínez-González6Antonio Rodríguez-Sinovas7Cardiovascular Diseases Research Group, Department of Cardiology, Vall d’Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d’Hebron 119-129, 08035 Barcelona, SpainCardiovascular Diseases Research Group, Department of Cardiology, Vall d’Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d’Hebron 119-129, 08035 Barcelona, SpainCentro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, SpainCentro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, SpainCardiovascular Diseases Research Group, Department of Cardiology, Vall d’Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d’Hebron 119-129, 08035 Barcelona, SpainCardiovascular Diseases Research Group, Department of Cardiology, Vall d’Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d’Hebron 119-129, 08035 Barcelona, SpainCentro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, SpainCardiovascular Diseases Research Group, Department of Cardiology, Vall d’Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Departament de Medicina, Pg. Vall d’Hebron 119-129, 08035 Barcelona, SpainConnexin 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<sup>fl/fl</sup> and Cx43<sup>Cre-ER(T)/fl</sup> 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, <i>p</i> < 0.05). However, animals with partial Cx43 deficiency (vehicle-treated Cx43<sup>Cre-ER(T)/fl</sup>) 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<sup>Cre-ER(T)/fl</sup> mice was associated with enhanced p38 MAPK activation and was not evident in Cx43 heterozygous (Cx43<sup>+/-</sup>) mice. In contrast, normalization of interstitial collagen in 4-OHT-treated Cx43<sup>Cre-ER(T)/fl</sup> 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<sup>Cre-ER(T)/fl</sup> 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.https://www.mdpi.com/2073-4409/8/10/1299angiotensin iifibrosiscollagenconnexin 43hypertrophy |
| spellingShingle | Laura Valls-Lacalle Corall Negre-Pujol Cristina Rodríguez Saray Varona Antoni Valera-Cañellas Marta Consegal Jose Martínez-González Antonio Rodríguez-Sinovas Opposite Effects of Moderate and Extreme Cx43 Deficiency in Conditional Cx43-Deficient Mice on Angiotensin II-Induced Cardiac Fibrosis Cells angiotensin ii fibrosis collagen connexin 43 hypertrophy |
| 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 | angiotensin ii fibrosis collagen connexin 43 hypertrophy |
| url | https://www.mdpi.com/2073-4409/8/10/1299 |
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