Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice
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López-Maderuelo, María Dolores
Jiménez-Borreguero, Luis Jesús
Armesilla, Ángel Luis
Redondo, Juan Miguel
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AbstractPrevious studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy. 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 cardiac hypertrophy in adults. Here, we exploited a mouse model of cardiac hypertrophy based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in cardiac hypertrophy in adulthood. AngII-induced cardiac hypertrophy 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 cardiac hypertrophy. Surprisingly, cardiac-specific delection of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII-induced cardiac fibrosis and apoptosis. Analysis of pro-fibrotic 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 pro-hypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.
CitationMartínez-Martínez S., Lozano-Vidal N., López-Maderuelo MD., Jiménez-Borreguero LJ., Armesilla ÁL., Redondo JM. (2018) 'Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice' FEBS Journal, 286 (1) pp. 46-65. doi: 10.1111/febs.14718
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