Opposite effects of moderate and extreme Cx43 deficiency in conditional Cx43-deficient mice on angiotensin II-induced cardiac fibrosis
Valls de Lacalle, Laura (Hospital Universitari Vall d'Hebron)
Rodríguez, Cristina (Institut d'Investigació Biomèdica Sant Pau)
Negre-Pujol, Corall (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Varona, Saray (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Valera Cañellas, Antoni (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Consegal, Marta (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Martínez-González, José (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Rodríguez-Sinovas, Antonio (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	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 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 α-SMA and SM22α 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Angiotensin II ; Fibrosis ; Collagen ; Connexin 43 ; Hypertrophy
Publicat a:	Cells, Vol. 8 (2019) , p. 1-17, ISSN 2073-4409

DOI: 10.3390/cells8101299
PMID: 31652649

17 p, 2.8 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Recerca Sant Pau
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