Opposite effects of moderate and extreme Cx43 deficiency in conditional Cx43-deficient mice on angiotensin II-induced cardiac fibrosis
Por:
Valls-Lacalle L., Negre-Pujol C., Rodríguez C., Varona S., Valera-Cañellas A., Consegal M., Martínez-González J., Rodríguez-Sinovas A.
Publicada:
1 ene 2019
Resumen:
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 a-SMA and SM22a 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. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Filiaciones:
Valls-Lacalle L.:
Cardiovascular 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, Barcelona, 08035, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Negre-Pujol C.:
Cardiovascular 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, Barcelona, 08035, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Rodríguez C.:
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Institut de Recerca del Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, 08041, Spain
Varona S.:
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), IIB-Sant Pau, Barcelona, 08041, Spain
Valera-Cañellas A.:
Cardiovascular 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, Barcelona, 08035, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Consegal M.:
Cardiovascular 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, Barcelona, 08035, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Martínez-González J.:
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), IIB-Sant Pau, Barcelona, 08041, Spain
Rodríguez-Sinovas A.:
Cardiovascular 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, Barcelona, 08035, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain
Green Published, gold, Gold, Green
|