1. Opposite effects of moderate and extreme Cx43 deficiency in conditional Cx43-deficient mice on angiotensin II-induced cardiac fibrosis
- Author
-
Valls de Lacalle, Laura, Rodríguez, Cristina, Negre-Pujol, Corall, Varona, Saray, Antoni Valera Cañellas, Consegal, Marta, Martínez-González, Jose, Rodríguez-Sinovas, Antonio, Universitat Autònoma de Barcelona, [Valls-Lacalle L, Negre-Pujol C, Valera-Cañellas A, Consegal M, Rodríguez-Sinovas A] Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain. Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. [Rodríguez C] Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. Institut de Recerca del Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain. [Varona S] Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Barcelona, Spain. Institut de Recerca del Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Fundació La Marató de TV3, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Generalitat de Catalunya, Rodríguez, Cristina [0000-0002-6472-5647], Rodríguez-Sinovas, Antonio [0000-0003-2930-8773], Rodríguez, Cristina, and Rodríguez-Sinovas, Antonio
- Subjects
0301 basic medicine ,collagen ,Cardiac fibrosis ,Connexin ,Muscle Proteins ,030204 cardiovascular system & hematology ,angiotensin ii ,Muscle hypertrophy ,connexin 43 ,Mice ,0302 clinical medicine ,Fibrosis ,Macrophage ,lcsh:QH301-705.5 ,Mice, Knockout ,Chemistry ,Angiotensin II ,Cell Differentiation ,General Medicine ,Eukaryota::animales::grupos de población animal::animales modificados genéticamente::ratones transgénicos::ratones noqueados [ORGANISMOS] ,Cardiovascular Diseases::Heart Diseases::Cardiomyopathies [DISEASES] ,cardiovascular system ,Collagen ,biological phenomena, cell phenomena, and immunity ,Cardiomyopathies ,hypertrophy ,hormones, hormone substitutes, and hormone antagonists ,medicine.medical_specialty ,p38 mitogen-activated protein kinases ,Miocardi - Malalties ,Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Membrane Transport Proteins::Connexins::Connexin 43 [CHEMICALS AND DRUGS] ,Article ,Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic::Mice, Knockout [ORGANISMS] ,03 medical and health sciences ,Internal medicine ,medicine ,aminoácidos, péptidos y proteínas::proteínas::proteínas de membranas::proteínas de transporte de membrana::conexinas::conexina 43 [COMPUESTOS QUÍMICOS Y DROGAS] ,Animals ,Myocardium ,fibrosis ,Hypertrophy ,Fibroblasts ,medicine.disease ,Connexines ,030104 developmental biology ,Endocrinology ,lcsh:Biology (General) ,Connexin 43 ,enfermedades cardiovasculares::enfermedades cardíacas::miocardiopatías [ENFERMEDADES] ,Myocardial fibrosis ,sense organs ,Models animals en la investigació - Abstract
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&ndash, 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 SM22&alpha, 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.
- Published
- 2019