Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice.

Autor: Martínez-Martínez S; Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.; Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Spain., Lozano-Vidal N; Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain., López-Maderuelo MD; Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.; Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Spain., Jiménez-Borreguero LJ; Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Spain.; Hospital de La Princesa, Madrid, Spain., Armesilla ÁL; Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Spain.; Research Institute in Healthcare Science, School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, UK., Redondo JM; Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.; Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Spain.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2019 Jan; Vol. 286 (1), pp. 46-65. Date of Electronic Publication: 2018 Dec 29.
DOI: 10.1111/febs.14718
Abstrakt: Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss-of-function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in CH in adulthood. AngII-induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for AngII-induced CH. Surprisingly, cardiac-specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII-induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that AngII-induced expression of Tgfβ family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac-specific calcineurin deletion. These results show that AngII induces a direct, calcineurin-dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.
(© 2018 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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